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New cancer treatment may reawaken the immune system

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Immunotherapy is a promising strategy to treat cancer by stimulating the body’s own immune system to destroy tumor cells, but it only works for a handful of cancers. MIT researchers have now discovered a new way to jump-start the immune system to attack tumors, which they hope could allow immunotherapy to be used against more types of cancer.

Their novel approach involves removing tumor cells from the body, treating them with chemotherapy drugs, and then placing them back in the tumor. When delivered along with drugs that activate T cells, these injured cancer cells appear to act as a distress signal that spurs the T cells into action.

“When you create cells that have DNA damage but are not killed, under certain conditions those live, injured cells can send a signal that awakens the immune system,” says Michael Yaffe, who is a David H. Koch Professor of Science, the director of the MIT Center for Precision Cancer Medicine, and a member of MIT’s Koch Institute for Integrative Cancer Research.

In mouse studies, the researchers found that this treatment could completely eliminate tumors in nearly half of the mice.

Yaffe and Darrell Irvine, who is the Underwood-Prescott Professor with appointments in MIT’s departments of Biological Engineering and Materials Science and Engineering, and an associate director of the Koch Institute, are the senior authors of the study, which appears today in Science Signaling . MIT postdoc Ganapathy Sriram and Lauren Milling PhD ’21 are the lead authors of the paper.

T cell activation

One class of drugs currently used for cancer immunotherapy is checkpoint blockade inhibitors, which take the brakes off of T cells that have become “exhausted” and unable to attack tumors. These drugs have shown success in treating a few types of cancer but do not work against many others.

Yaffe and his colleagues set out to try to improve the performance of these drugs by combining them with cytotoxic chemotherapy drugs, in hopes that the chemotherapy could help stimulate the immune system to kill tumor cells. This approach is based on a phenomenon known as immunogenic cell death, in which dead or dying tumor cells send signals that attract the immune system’s attention.

Several clinical trials combining chemotherapy and immunotherapy drugs are underway, but little is known so far about the best way to combine these two types of treatment.

The MIT team began by treating cancer cells with several different chemotherapy drugs, at different doses. Twenty-four hours after the treatment, the researchers added dendritic cells to each dish, followed 24 hours later by T cells. Then, they measured how well the T cells were able to kill the cancer cells. To their surprise, they found that most of the chemotherapy drugs didn’t help very much. And those that did help appeared to work best at low doses that didn’t kill many cells.

The researchers later realized why this was so: It wasn’t dead tumor cells that were stimulating the immune system; instead, the critical factor was cells that were injured by chemotherapy but still alive.

“This describes a new concept of immunogenic cell injury rather than immunogenic cell death for cancer treatment,” Yaffe says. “We showed that if you treated tumor cells in a dish, when you injected them back directly into the tumor and gave checkpoint blockade inhibitors, the live, injured cells were the ones that reawaken the immune system.”

The drugs that appear to work best with this approach are drugs that cause DNA damage. The researchers found that when DNA damage occurs in tumor cells, it activates cellular pathways that respond to stress. These pathways send out distress signals that provoke T cells to leap into action and destroy not only those injured cells but any tumor cells nearby.

“Our findings fit perfectly with the concept that ‘danger signals’ within cells can talk to the immune system, a theory pioneered by Polly Matzinger at NIH in the 1990s, though still not universally accepted,” Yaffe says.  

Tumor elimination

In studies of mice with melanoma and breast tumors, the researchers showed that this treatment eliminated tumors completely in 40 percent of the mice. Furthermore, when the researchers injected cancer cells into these same mice several months later, their T cells recognized them and destroyed them before they could form new tumors.

The researchers also tried injecting DNA-damaging drugs directly into the tumors, instead of treating cells outside the body, but they found this was not effective because the chemotherapy drugs also harmed T cells and other immune cells near the tumor. Also, injecting the injured cells without checkpoint blockade inhibitors had little effect.

“You have to present something that can act as an immunostimulant, but then you also have to release the preexisting block on the immune cells,” Yaffe says.

Yaffe hopes to test this approach in patients whose tumors have not responded to immunotherapy, but more study is needed first to determine which drugs, and at which doses, would be most beneficial for different types of tumors. The researchers are also further investigating the details of exactly how the injured tumor cells stimulate such a strong T cell response.

The research was funded, in part, by the National Institutes of Health, the Mazumdar-Shaw International Oncology Fellowship, the MIT Center for Precision Cancer Medicine, and the Charles and Marjorie Holloway Foundation.

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New study finds triple-negative breast cancer tumors with an increase in immune cells have lower risk of recurrence after surgery

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By Kelley Luckstein

A new multicenter, international study suggests that people who have early-stage  triple-negative breast cancer  (TNBC) and high levels of immune cells within their tumors may have a lower risk of recurrence and better survival rates even when not treated with chemotherapy. The  study  was published today in the Journal of American Medical Association (JAMA).

TNBC is a breast cancer subtype that does not respond to drugs that target the estrogen receptor or the HER2 protein. It grows rapidly, is more likely to spread beyond the breast before diagnosis and is more likely to recur than other breast cancers. TNBC represents about 15% of all breast cancers and is more common in younger people and in women of African American, Hispanic and Indian descent. Immune cells, also known as tumor-infiltrating lymphocytes, or TILs, are naturally existing immune system cells that can move from the bloodstream into a tumor and can recognize and destroy cancer cells.

"This is an important finding because it highlights that the abundance of TILs in breast tissue is a prognostic biomarker in people with early-stage triple-negative breast cancer, even when chemotherapy is not administered," says  Roberto Leon-Ferre, M.D. , a breast medical oncologist at  Mayo Clinic Comprehensive Cancer Center  and first author of the study. "The study's findings may inspire future clinical trials to explore whether patients with a favorable prognosis (high TILs) can avoid intensive chemotherapy regimens."

"This meta-analysis confirms robustly the prognostic value of TILs that we have previously reported in TNBC patients treated with chemotherapy and expands it to patients treated without chemotherapy," says Sarah Flora Jonas, Ph.D., a statistician at  Gustave Roussy  and co-first author of the study. "Future studies may allow the use of this biomarker along with standard clinicopathological factors to inform treatment decisions in TNBC patients."

"Of interest, the first report suggesting that an increased number of immune cells being associated with better prognosis in breast cancer patients was described by doctors at Mayo Clinic more than 100 years ago," says Roberto Salgado, M.D., co-chair of the International Immuno-Oncology Biomarker Working Group; co-lead of the study; and pathologist from the Peter MacCallum Cancer Centre, Melbourne, Australia, and ZAS Hospitals, Antwerp, Belgium. "It took a global effort and a century later to reexamine this biomarker and bring it closer to application in patient care."

"TILs are not currently measured or reported in the routine examination of tissue samples of breast cancer," says co-senior author,  Matthew Goetz, M.D. , a medical oncologist at Mayo Clinic Comprehensive Cancer Center and the Erivan K. Haub Family Professor of Cancer Research Honoring Richard F. Emslander, M.D. "While prior studies have focused on measuring TILs in people treated with chemotherapy, this is the largest study to comprehensively demonstrate that the presence of TILs influences the natural behavior of breast cancer in people who have surgery and/or radiation with no additional medical treatment."

For this study, Mayo Clinic and Gustave Roussy researchers, in collaboration with the International Immuno-Oncology Biomarker Working Group, led 11 additional groups to collect data on 1,966 participants with early-stage TNBC who only underwent surgery with or without radiation therapy but did not receive chemotherapy. The participants had been followed for a median of 18 years. The results showed that higher levels of TILs in breast cancer tissue were associated with lower recurrence rates among participants with early-stage TNBC.

"Five years after surgery, 95% of participants with small tumors, stage 1 TNBC, and whose tumors had high TILs were alive, compared to 82% of patients whose tumors had low TILs. Importantly, the breast cancer recurrence rate was significantly lower among patients whose tumors had high TILs," says co-senior author,  Stefan Michiels, Ph.D. , head of Oncostat team, Gustave Roussy, Inserm U1018, University Paris-Saclay. "With nearly 2,000 participants involved in the study, we have now assembled the largest international cohort across three continents of people with TNBC in which the primary treatment was surgery without chemotherapy."

"The results of this study could lead to a recommendation to include TILs in the pathology reports of early-stage TNBC worldwide, as it has the potential to inform clinicians and patients when they discuss treatment options," says Dr. Salgado.

Furthermore, this biomarker would only require a visual evaluation by a pathologist looking through a microscope, meaning there are no additional costs associated with identifying the presence of immune cells. This could be particularly beneficial to regions with limited resources, adds Dr. Leon-Ferre.

Most people with early-stage TNBC undergo chemotherapy either before or after surgery, including people with stage 1 breast cancer. Most people receive multiple chemotherapy drugs in combination, which can cause significant side effects. Currently, the main factors considered to determine the course of chemotherapy treatment for each person are the tumor size and whether the cancer has spread to the lymph nodes. However, the authors identified that the number of TILs further influences the risk of future recurrence.

The researchers plan to evaluate TILs as biomarkers in prospective clinical trials evaluating chemotherapy selection based on TIL levels. Ongoing efforts to conduct additional research with other potential biomarkers are underway.

For a complete list of authors, disclosures and funding, see the full paper  here .

Learn more about breast cancer and find a clinical trial at Mayo Clinic.

Join the Breast Cancer Support Group on Mayo Clinic Connect , an online community moderated by Mayo Clinic for patients and caregivers.

Also, read these articles:

• Understanding triple-negative breast cancer and its treatment
• 17-gene signature linked to remission after triple-negative breast cancer treatment

A version of this article was originally published as a press release on the Mayo Clinic News Network .

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June 3, 2024

Suresh Ramalingam, MD, Winship Cancer Institute of Emory University's executive director, presents results of the LAURA trial at the 2024 ASCO Annual Meeting.

In a recent study led by   Suresh Ramalingam, MD , executive director of Winship Cancer Institute of Emory University, a new drug has shown remarkable promise in treating patients with a specific type of advanced lung cancer. Osimertinib, produced by AstraZeneca under the brand name Tagrisso, significantly extends the time patients live without their cancer worsening, offering the first effective therapy and new hope for those with stage III non-small cell lung cancer (NSCLC) who have mutations in the epidermal growth factor receptor (EGFR), a protein that controls cell division and survival.

Key findings

Patients participating in the trial had already undergone standard treatments, including chemotherapy and radiation, without their cancer progressing further. Participants were randomly assigned to receive either osimertinib or a placebo.

The results were compelling: patients taking osimertinib experienced a median progression-free survival of 39.1 months, compared to just 5.6 months for those on the placebo. This means that osimertinib reduced the risk of disease progression or death by an impressive 84%.

Broader impacts

Osimertinib is the first and only EGFR inhibitor to show such a benefit in the stage III setting, extending progression-free survival by more than three years. The study demonstrated a clinically meaningful benefit across various patient subgroups, including differences in sex, race, type of EGFR mutation, age, smoking history and prior treatments.

While overall survival data are still maturing, early results indicate a favorable trend for osimertinib. The trial will continue to monitor overall survival as a secondary endpoint.

“The impressive progression-free survival results from the LAURA Phase III trial represent a major breakthrough for patients with stage III EGFR-mutated lung cancer for whom no targeted treatments are available,” says Ramalingam. “Osimertinib delayed the risk of disease progression or death by an unprecedented 84% and should become the new standard of care for patients in this setting based on these data.”

Safety and approval

Regarding safety, 35% of patients on osimertinib experienced serious side effects, compared to 12% in the placebo group. The most common issue was radiation pneumonitis, an inflammation of the lungs caused by radiation therapy, affecting nearly half of the patients in both groups. Importantly, no new safety concerns were identified.

Osimertinib is already approved as a monotherapy in over 100 countries, including the US, EU, China, and Japan, for various stages and types of EGFR-mutated NSCLC. These latest findings further solidify its role as a crucial treatment option.

The positive results from the LAURA Phase III trial underscore the importance of early testing and diagnosis in lung cancer, which remains the leading cause of cancer death worldwide, accounting for about one-fifth of all cancer deaths. Each year, an estimated 2.4 million people are diagnosed with lung cancer globally, with non-small cell lung cancer (NSCLC) being the most common form.

EGFR mutations are found in a significant subset of NSCLC patients, particularly in Asia, making targeted therapies like osimertinib vital in treatment. “Tagrisso extended progression-free survival by more than three years in this potentially curative setting, reinforcing the need to test and diagnose patients early. These practice-changing data cement the powerful impact Tagrisso can make as backbone therapy in EGFR-mutated lung cancer,” says Susan Galbraith, executive vice president of oncology R&D at AstraZeneca, which funded the study.

For more information about the clinical trial, details can be found under the identifier   NCT03521154 .

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After 40 years of smoking, she survived lung cancer thanks to new treatments

Yuki Noguchi

Denise Lee on her last day of chemo. In addition to chemo and surgery, she was treated with immunotherapy. She's currently in remission. Denise Lee hide caption

Denise Lee on her last day of chemo. In addition to chemo and surgery, she was treated with immunotherapy. She's currently in remission.

Denise Lee grew up in Detroit in the mid-1970s and went to an all-girls Catholic high school. She smoked her first cigarette at age 14 at school, where cigarettes were a popular way of trying to lose weight.

Instead, her nicotine addiction lasted four decades until she quit in her mid-50s.

"At some point it got up as high as 2.5 packs a day," Lee, 62, recalls.

Yet she didn't think about lung cancer risk — until she saw a billboard urging former smokers to get screened. Lee, a retired lawyer living in Fremont, Calif., used to drive past it on her way to work.

"The thing that caught my attention was the fact that it was an African American female on the front," she recalls.

Shots - Health News

The american cancer society says more people should get screened for lung cancer.

She eventually got the low-dose CT scan recommended for current and former smokers. When doctors found an early, but dangerous, tumor, Lee cried and panicked. Her mother had cared for her father, who'd died of prostate cancer. "My biggest concern was telling my mom," she says.

But that was six years ago, and Lee is cancer free today. Surgery removed the 2-inch tumor in her lung, then new treatments also boosted her immune system, fighting off any recurrence.

Lung cancer remains the most lethal form of the disease, killing about 135,000 Americans a year – more than breast, prostate and colon cancer combined – which is why many people still think of a diagnosis as synonymous with a death sentence. But with new treatments and technology, the survival rates from lung cancer are dramatically improving, allowing some patients with relatively late-stage cancers to live for years longer.

"If you're gonna have lung cancer, now is a good time," Lee says of the advances that saved her.

Denise Lee has been cancer-free for six years. She says she's grateful she got screened and caught her lung cancer early enough that treatment has been effective. Denise Lee hide caption

Denise Lee has been cancer-free for six years. She says she's grateful she got screened and caught her lung cancer early enough that treatment has been effective.

The key breakthrough, says Robert Winn, a lung cancer specialist at Virginia Commonwealth University, is the ability to better pinpoint the mutations of a patient's particular form of cancer. In the past, treatments were blunt tools that caused lots of collateral damage to healthy parts of the body while treating cancer.

"We've gone from that to molecular characterization of your lung cancer, and it has been a game changer," Winn says. "This is where science and innovation has an impact."

One of those game-changing treatments is called targeted therapy . Scientists identify genetic biomarkers in the mutated cancer cells to target and then deliver drugs that attack those targets, shrinking tumors.

CRISPR gene-editing may boost cancer immunotherapy, new study finds

Another is immunotherapy, usually taken as a pill, which stimulates the body's own defense system to identify foreign cells, then uses the immune system's own power to fight the cancer as if it were a virus.

As scientists identify new cancer genes, they're creating an ever-broader array of these drugs.

Combined, these treatments have helped increase national survival rates by 22% in the past five years – a rapid improvement over a relatively short time, despite the fact that screening rates are very slow to increase. Winn says as these treatments get cheaper and readily available, the benefits are even reaching rural and Black populations with historic challenges accessing health care.

The most remarkable thing about the drugs is their ability to, in some cases, reverse late-stage cancers. Chi-Fu Jeffrey Yang, a thoracic surgeon at Massachusetts General Hospital and faculty at Harvard Medical School, recalls seeing scans where large dark shadows of tumor would disappear: "It was remarkable to see the lung cancer completely melting away."

To Yang, such progress feels personal. He lost his beloved grandfather to the disease when Yang was in college. If he were diagnosed today, he might still be alive.

"Helping to take care of him was a big reason why I wanted to be a doctor," Yang says.

But the work of combating lung cancer is far from over; further progress in lung cancer survival hinges largely on getting more people screened.

Low-dose CT scans are recommended annually for those over 50 who smoked the equivalent of a pack a day for 20 years. But nationally, only 4.5% of those eligible get those scans , compared to rates of more than 75% for mammograms.

Andrea McKee, a radiation oncologist and spokesperson for the American Lung Association, says part of the problem is that lung cancer is associated with the stigma of smoking. Patients often blame themselves for the disease, saying: "'I know I did this to myself. And so I don't I don't think I deserve to get screened.'"

McKee says that's a challenge unique to lung cancer. "And it just boggles my mind when I hear that, because, of course, nobody deserves to die of lung cancer."

Denise Lee acknowledges that fear. "I was afraid of what they would find," she admits. But she urges friends and family to get yearly scans, anyway.

"I'm just so grateful that my diagnosis was early because then I had options," she says. "I could have surgery, I could have chemotherapy, I could be a part of a clinical trial."

And all of that saved her life.

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Cancer patients often do better with less intensive treatment, research shows

Scaling back treatment for three kinds of cancer can make life easier for patients without compromising outcomes, doctors reported at the world’s largest cancer conference .

It’s part of a long-term trend toward studying whether doing less — less surgery, less chemotherapy or less radiation — can help patients live longer and feel better. The latest studies involved ovarian and esophageal cancer and Hodgkin lymphoma.

Thirty years ago, cancer research was about doing more, not less. In one sobering example, women with advanced breast cancer were pushed to the brink of death with massive doses of chemotherapy and bone marrow transplants. The  approach didn’t work  any better than chemotherapy and patients suffered.

Now, in a quest to optimize cancer care, researchers are asking: “Do we need all that treatment that we have used in the past?”

It’s a question, “that should be asked over and over again,” said Dr. Tatjana Kolevska, medical director for the Kaiser Permanente National Cancer Excellence Program, who was not involved in the new research.

Often, doing less works because of improved drugs.

“The good news is that cancer treatment is not only becoming more effective, it’s becoming easier to tolerate and associated with less short-term and long-term complications,” said Dr. William G. Nelson of Johns Hopkins School of Medicine, who was also not involved in the new research.

Latest news on cancer treatment

• Cancer-fighting antibodies inject chemo directly into tumor cells, upping effectiveness.
• Long-term study shows 'remarkable' treatment helps patients with deadly nonsmoking-related lung cancer.
• FDA approves groundbreaking treatment for advanced melanoma.

Studies demonstrating the trend were discussed over the weekend at an American Society of Clinical Oncology conference in Chicago. Here are the highlights:

Ovarian cancer

French researchers found that it’s safe to avoid removing lymph nodes that appear healthy during surgery for advanced ovarian cancer. The study compared the results for 379 patients — half had their lymph nodes removed and half did not. After nine years, there was no difference in how long the patients lived and those with less-extreme surgery had fewer complications, such as the need for blood transfusions. The research was funded by the National Institute of Cancer in France.

Esophageal cancer

This German study looked at 438 people with a type of cancer of the esophagus that can be treated with surgery. Half received a common treatment plan that included chemotherapy and surgery on the esophagus, the tube that carries food from the throat to the stomach. Half got another approach that includes radiation too. Both techniques are considered standard. Which one patients get can depend on where they get treatment.

After three years, 57% of those who got chemo and surgery were alive, compared to 51% of those who got chemo, surgery and radiation. The German Research Foundation funded the study.

Hodgkin lymphoma

A comparison of two chemotherapy regimens for advanced Hodgkin lymphoma found the less intensive treatment was more effective for the blood cancer and caused fewer side effects.

After four years, the less harsh chemo kept the disease in check in 94% of people, compared to 91% of those who had the more intense treatment. The trial included 1,482 people in nine countries — Germany, Austria, Switzerland, the Netherlands, Denmark, Sweden, Norway, Australia and New Zealand — and was funded by Takeda Oncology, the maker of one of the drugs used in the gentler chemo that was studied.

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• v.5(4); 2021 Jul

Recent developments in cancer research: Expectations for a new remedy

1 Department of Surgery and Science, Kyushu University, Fukuoka Japan

Qingjiang Hu

Yuta kasagi, masaki mori.

Cancer research has made remarkable progress and new discoveries are beginning to be made. For example, the discovery of immune checkpoint inhibition mechanisms in cancer cells has led to the development of immune checkpoint inhibitors that have benefited many cancer patients. In this review, we will introduce and describe the latest novel areas of cancer research: exosomes, microbiome, immunotherapy. and organoids. Exosomes research will lead to further understanding of the mechanisms governing cancer proliferation, invasion, and metastasis, as well as the development of cancer detection and therapeutic methods. Microbiome are important in understanding the disease. Immunotherapy is the fourth treatment in cancer therapy. Organoid biology will further develop with a goal of translating the research into personalized therapy. These research areas may result in the creation of new cancer treatments in the future.

Cancer research has made remarkable progress and new discoveries are beginning to be made. In this review, we will introduce and describe the latest novel areas of cancer research: exosomes, microbiomes, immunotherapy, and organoids.

1. INTRODUCTION

The cancer research field has developed significantly through use of new equipment and technology. One example of new technology is Next‐Generation Sequencing (NGS). Also known as high‐throughput sequencing, NGS is the catch‐all term used to describe a number of different modern nucleic acid sequencing technologies. These methods allow for much quicker and cheaper sequencing of DNA and RNA compared with the previously used Sanger sequencing, and as such have revolutionized the study of genomics and molecular biology. NGS also allows for easier detection of mutations in cancer samples, leading to development of many new agents that can be used to treat patients. For example, if the RAS gene status is detected as wild type in a colorectal cancer patient, then an anti‐EGFR antibody, such as cetuximab or panitumumab, can be used for treatment.

A liquid biopsy, also known as fluid biopsy or fluid phase biopsy, is the sampling and analysis of non‐solid biological tissue, primarily blood. 1 It is being used as a novel way to detect cancer. Like a traditional biopsy, this type of technique is mainly used as a diagnostic and monitoring tool for diseases, and also has the added benefit of being largely noninvasive. Therefore, liquid biopsies can be performed more frequently, allowing for better tracking of tumors and mutations over a duration of time. This technique may also be used to validate the effectiveness of a cancer treatment drug by taking multiple liquid biopsy samples in the span of a few weeks. It may also prove to be beneficial for monitoring relapse in patients after treatment.

Novel devices and drugs have also been developed and used for cancer treatment. For surgery procedures, robotic‐assisted laparoscopic surgery has evolved and made it possible to visualize the fine movement of the forceps in three dimensions. This method is now used in esophageal, gastric, and rectal cancer surgeries in Japan. 2 , 3 , 4

Recently, immunotherapy became an additional method for treating cancer patients. The discovery of the immune checkpoint by Dr Honjo led to the development of immune checkpoint inhibitors. 5 Despite these developments, gastrointestinal cancers are still a major problem in need of new treatment methods. In this review, we introduce and describe four new areas of cancer research that may contribute to cancer treatment in the future: exosomes, microbiome, immunotherapy, and organoids.

2. AN APPLICATION OF EXOSOME RESEARCH IN CANCER THERAPY

An exosome is a small particle that is secreted by cells. Its size can range from 50 to 150 nm and has a surface consisting of proteins and lipids that originate from the cell membrane. Additionally, proteins and nucleic acids, such as DNA, microRNAs, and mRNAs, can be found inside the exosome as its “cargo.” 6 Recently, many researchers have discovered that exosomes are involved in the mechanisms of various diseases. As mentioned above, various functional compounds, such as microRNAs, mRNAs, and proteins, can be contained within exosomes. 7 , 8 Many cells use secretion of exosomes to communicate with one another, and these exosomes can even reach distant cells. Cancer cells can also secrete exosomes that contain molecules beneficial to cancer growth. For example, microRNAs found in cancer exosomes can modulate gene expression to induce angiogenesis in the tumor microenvironment, which supports metastasis. 9 Exosomes released from cancer cells can also reportedly break the blood‐brain barrier, which makes it contribute to brain metastasis. 10 , 11 Cancer cells themselves are similarly affected by the exosomes secreted by the surrounding normal cells. 12 In one case, the exosomes secreted by bone marrow‐delivered mesenchymal stem cells can force cancer cells into a dormant state. 13 These dormant cancer cells become resistant to chemotherapy and are involved in long‐term disease recurrence. Thus, exosomes are deeply involved in cancer proliferation, invasion, and metastasis, as well as in the formation of the tumor microenvironment and pre‐metastatic niche. 13 Further research on cancer‐related exosomes is ongoing.

Knowledge of exosomes can be applied to cancer treatment. If the secretion of exosomes from cancer cells can be prevented, then signal transduction supporting the formation of the tumor microenvironment and pre‐metastatic niche can be blocked. Work focusing on the removal of cancer exosomes is now ongoing. 14

Exosomes can also be utilized for cancer diagnosis. Exosomes secreted by many cell types are found in various body fluids, such as blood and urine. Capturing and analyzing exosomes from cancer cells can be used to detect the presence of disease. 15 Obtaining blood or urine from patients is not very invasive or painful. Since many molecules, such as various proteins, DNA, and microRNAs, can be found in exosomes from normal cells, it is important to distinguish them from cancer‐related ones. If exosomes are to be used for cancer diagnosis, then specific biomarkers need to be discovered. Additionally, the development of a method to detect these exosomes must be done. Currently, exosome detection methods for exosomes abundantly found in the serum of colorectal and pancreatic cancer patients, as well as exosomes found in the urine of bladder cancer patients, are being developed. 16 , 17 Thus, further understanding of the mechanisms governing cancer proliferation, invasion, and metastasis, as well as the development of cancer detection and therapeutic methods, is significantly affected by exosome research.

3. MICROBIOME IN CANCER RESEARCH

A large number of microorganisms inhabit the human body. These microorganisms include bacteria, viruses, and fungi. Among them, bacteria have the most important relationship with the human body. Bacteria can live anywhere within the human body, including the digestive tract, respiratory system, and oral cavity. 18 , 19 , 20 In particular, bacteria in the digestive tract are rich in type and number, 21 with possibly 1000 types and more than 100 trillion individual bacterial cells present. 22 , 23 The overall population of various bacteria found in the human intestine is referred to as the “intestinal flora.” Recently, the terms “microbiota” or “microbiome” have also been widely used.

Recent advancements with NGS have led to a much more precise understanding of the intestinal microbiome. 24 The bacteria in the human microbiome mainly belong to four phyla: Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteri. Of these, Firmicutes and Bacteroidetes are the most dominant species. It is reported that microbiome vary depending on age and race. 25 , 26 Dysbiosis is a condition in which the diversity of the microbiome is reduced. Dysbiosis is reportedly involved in various diseases such as inflammatory bowel disease, colorectal cancer, obesity, diabetes, and allergic diseases. 27 , 28 , 29 For example, bacteria such as Atopobium parvulum and Actinomyces odontolyticus increase in number during the early stages of colorectal cancer (adenomas or intramucosal cancers) and decrease in number during cancer progression. 30 This suggests that a specific microbiome is associated with early stages of colorectal cancer development, which may be useful knowledge for early cancer detection.

Various studies have also been conducted to elucidate the relationship between the microbiome and the human immune system. 31 The IgA antibody, which is one of the most important elements in the intestinal immune system, is believed to play a role in the elimination of pathogens and maintenance of the intestinal environment. The IgA antibody recognizes, eliminates, and neutralizes pathogenic bacteria and toxins. It also maintains a symbiotic relationship by recognizing and binding to the normal microbiome of the host. 32 Mice lacking a microbiome have reduced production of the IgA antibody. A microbiome is required for IgA antibody differentiation. Recent studies have identified W27IgA antibodies that have the ability to bind to various bacteria. 33 Oral administration of a W27IgA antibody to enteritis model mice suppressed enteritis by altering the microbiome. This W27IgA antibody can recognize a part of the amino acid sequence of serine hydroxymethyl transferase, which is a metabolic enzyme involved in bacterial growth. The W27IgA antibody can suppress the growth of E coli by binding to them. However, the W27IgA antibody does not bind to bacteria that suppress enteritis, such as bifidobacteria and lactic acid bacteria. 33 Thus, the microbiome is deeply involved in human intestinal immunity. Recently, it is having been established that the microbiome is not only involved in intestinal immunity, but also in the systemic immune system.

As the analysis of the microbiome progresses, the pathophysiology of various diseases, such as cancers, and its relationship with the regulatory function of the human immune system will be further elucidated. It has been demonstrated that F nucleatum plays a role in the development and progression of colon adenomas and colorectal cancer. It is also related to lymph node metastases and distant metastasis. 34 , 35 Also, microbiome is associated with hepatocellular carcinoma. 36 Studying microbiome will give us some clue in the development and remedy for gastrointestinal cancers (Table  1 ).

Gastrointestinal cancer and their related microbiome

4. THE RISE OF IMMUNOTHERAPY IN CANCER TREATMENT

For many years, surgery, chemotherapy, and radiation therapy were the main methods of cancer treatment. In addition to these therapies, immunotherapy has recently attracted great attention worldwide (Table  2 ). 37 , 38 Under normal circumstances, a cancer antigen will activate the patient's immune system to attack the cancer cells. However, sometimes the immune system does not recognize the cancer cells as non‐self, or it simply fails to attack them. This can result in the development and progression of cancer.

Immune checkpoint inhibitors

Although therapies that activate the immune system against cancer cells have been studied for a long time, the use of the patient's own immune system for cancer treatment was not established. Recently, the effectiveness of both immune checkpoint inhibition therapy and chimeric antigen receptor (CAR)‐T cell therapy has proved to be promising. 39 , 40 Immunotherapy has moved to the forefront of cancer treatment strategies.

There are two major reasons why proving the efficacy of cancer immunotherapies was difficult for some time. First, cancer immunity is strongly suppressed. Signal transduction from immune checkpoint compounds, such as PD‐1 and CTLA4, strongly inhibits cytotoxic T cells (CTLs). 38 This checkpoint mechanism can prevent the immune system from attacking cancer cells. The development of immune checkpoint inhibitors has arisen from the discovery of this mechanism. Inhibition of immune checkpoint molecules with neutralizing antibodies can release the suppression of cancer‐specific CTLs, activate immunity, and promote cancer elimination. The effectiveness of immune checkpoint antibodies has been confirmed and clinically applied to many solid cancers such as melanoma, 41 lung cancer, 42 urothelial cancer, 43 gastric cancer, 44 and esophageal cancer. 45 In addition to PD‐1 and CTLA4, new immune checkpoint molecules, such as LAG3, TIGIT, and SIRPA, are also being actively studied. 46 , 47 , 48 Although this therapy is promising, the cancer cases who respond to these therapies are limited. This is because use of this therapy requires the presence of cancer‐specific CTLs in the patient's body. To maximize the therapeutic effect, it is desirable to select appropriate cases and develop useful biomarkers.

The second difficulty for immunotherapy is that T cells do not recognize specific cancer cell antigens and immune accelerators are too weak. One goal of CAR‐T cell therapy is to strengthen the immune accelerator by administering CTLs to the patient's body that recognize specific cancer cell‐specific antigens. A CAR is prepared by fusing a single chain Fv (scFv), derived from a monoclonal antibody that recognizes a specific antigen expressed by cancer cells, with CD3z and costimulatory molecules (CD28, 4‐1BB, and others). Next, the CAR is introduced to the T cells obtained from a cancer patient and CAR‐T cells are made. CAR‐T cells recognize the specific antigen of the cancer cells and are activated to damage these cells. CAR‐T cells recognize cancer‐specific antigens with high antibody specificity and attack the respective cancer cells with strong cytotoxic activity and high proliferative activity. CAR‐T therapy is effective in blood cancers such as B‐cell acute lymphoblastic leukemia and myeloma. 49 , 50 While CAR‐T cell therapy has a high therapeutic effect, a frequent and serious adverse event called cytokine release syndrome has been observed in some patients. 51 , 52 The development of a technique for suppressing the occurrence of cytokine release syndrome is anticipated. In addition, the development of CAR‐T cell therapies for solid tumors is ongoing.

Recently, there was new progress made in treating gastrointestinal cancer patients. For MSI‐H colorectal cancer, the combination therapy with nivolumab and ipilimumab was approved. From the nivolumab plus ipilimumab cohort of CheckMate‐142, progression‐free survival rates were 76% (9 months) and 71% (12 months); respective overall survival rates were 87% and 85% which were quite high. This new treatment will benefit MSI‐H colorectal cancer patients. 53

Thus, it is expected that further understanding of cancer immune mechanisms and the development of various immunotherapies will contribute to great progress in cancer treatment.

One problem for immunotherapy is that there is no certain predictive biomarker. It was thought that the expression of PD‐1 or PD‐L1 would predict the effect. However, this was not the case. To find a new biomarker, we assessed the cytolytic activity (CYT) score. The CYT score is a new index of cancer immunity calculated from the mRNA expression levels of GZMA and PRF1. We are now evaluating CYT score in gastric cancer patients (data not published). The development in the biomarker search will benefit many gastrointestinal cancer patients.

5. ADVANTAGES FOR USING ORGANOIDS IN CANCER RESEARCH

The three‐dimensional (3D) organoid system is a cell culture‐based, novel, and physiologically relevant biologic platform. 54 An organoid is a miniaturized and simplified version of an organ that is produced in vitro in 3D and shows realistic microanatomy. With only one to a few cells isolated from tissue or cultured cells as the starting material, organoids are grown and passaged in a basement membrane matrix, which contributes to their self‐renewal and differentiation capacities. 54 , 55 The technique used for growing organoids has rapidly improved since the early 2010s with the advent of the field of stem cell biology. The characteristics of stem, embryonic stem cells (ES cells), or induced pluripotent stem cells (iPS cells) that allow them to form an organoid in vitro are also found in multiple types of carcinoma tissues and cells. Therefore, cancer researchers have applied ES cells or iPS cells in their field. 56 , 57 , 58

Organoid formation generally requires culturing stem cells or their progenitor cells in 3D. 54 , 55 The morphological and functional characteristics of various types of carcinoma tissue have been recapitulated in organoids that were generated from single‐cell suspensions or cell aggregates. These suspensions or aggregates were isolated from murine and human tissues or cultured cells, as well as from cancer stem cells propagated in culture. The structures of the organoids show the potential of cancer stem cell self‐renewal, proliferation, and differentiation abilities, and also provide insights into the roles of molecular pathways and niche factors that are essential in cancer tissues. 56 , 57 , 59 , 60 , 61 , 62 The organoid system also has been utilized for studying multiple biological processes, including motility, stress response, cell‐cell communications, and cellular interactions that involve a variety of cell types such as fibroblasts, endothelial cells, and inflammatory cells. These interactions are mediated via cell surface molecules, extracellular matrix proteins, and receptors in the microenvironment under homeostatic and pathologic conditions.

Although the organoid system is a complex and not effortless procedure that requires specific media, supplements, and many tricky techniques, 58 , 63 application of this system has been extended to a variety of cell types from different carcinomas (colorectal, pancreatic, prostate, breast, ovary, and esophageal cancers). 56 , 57 , 59 , 60 , 61 An organoid is generally induced within a few days to weeks, and is faster and less costly than the murine xenograft assay. Furthermore, applying novel genetic manipulations (e.g. CRISPR‐Cas9) can be carried out in the organoid system. 64 , 65

Kasagi et al modified keratinocyte serum‐free medium to grow 3D organoids from endoscopic esophageal biopsies, immortalized human esophageal epithelial cells, and murine esophagi. Esophageal 3D organoids serve as a novel platform to investigate regulatory mechanisms in squamous epithelial homeostasis in the context of esophageal cancers. 64

We anticipate that many experimental results that utilize the organoid system will be published in the future.

The 3D organoid system has emerged in the past several years as a robust tool in basic research with the potential to be used for personalized medicine. 66 By passaging dissociated primary structures to generate secondary 3D organoids, this system can be performed using live tissue pieces obtained from biopsies, operative‐resected specimens, or even frozen tissues. This method has the potential to transform personalized therapy. For example, in the case of cancer recurrence, an effective chemotherapy can be selected by testing the chemotherapeutic sensitivity of cancer‐derived organoids from an individual patient's tissue stocks. In many cases, a patient's organoid accumulation is helpful for testing the sensitivity of novel therapeutic agents for treating carcinoma. 66 Hence, it appears that organoid biology will further develop with a goal of translating the research into personalized therapy.

6. SUMMARY AND FUTURE DIRECTIONS

This review describes four new cancer‐related studies: exosomes, microbiome, immunotherapy, and organoids (Figure  1 ).

The summary of the four cancer research areas. In this figure the summary of the four cancer research areas is shown: exosome, microbiome, immunotherapy, and organoid research

Since exosomes are released in blood or urine, if the capturing system is established, it will be a less invasive test to diagnose cancer. In the present, the presence of circulating tumor DNA (ctDNA) is one of the tools to detect the minimal residual disease. However, since ctDNA is only DNA, it is difficult to spread to cancer research. In that respect, as exosomes include not only DNA but also other nucleic acids and proteins, this will be a new tool for cancer research such as the diagnosis of early cancer.

Microbiome may lead to improved cancer diagnosis and treatment. Detecting a specific microbiome in a gastrointestinal tract may predict a specific cancer. And changing microbiome in some way may result in preventing cancer development.

Organoids may help address the problem of drug resistance, and also lead to the development of personalized therapy. However, producing organoids takes time and testing the drug resistance may take more time. If we could overcome these problems, the research into organoids can contribute to overcoming cancer.

As shown in Table  3 , many new studies and findings are reported into this field of research. These four novel cancer research areas will make many contributions to the diagnosis and treatment of cancer.

Recent studies on exosome, microbiome, immunotherapy, and organoids

Conflict of Interest: All the authors have no conflict of interest to disclose.

ACKNOWLEDGMENTS

We thank Dr Hirofumi Hasuda and Dr Naomichi Koga for their help in preparing this manuscript. We also thank J. Iacona, PhD, from Edanz Group for editing a draft of this manuscript.

Ando K, Hu Q, Kasagi Y, Oki E, Mori M. Recent developments in cancer research: Expectations for a new remedy . Ann Gastroenterol Surg . 2021; 5 :419–426. 10.1002/ags3.12440 [ PMC free article ] [ PubMed ] [ CrossRef ] [ Google Scholar ]

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Clear as a bell

Women who follow Mediterranean diet live longer

Harvard-led study IDs statin that may block pathway to some cancers

Dramatic rise in cancer in people under 50.

Kira Sampson

Brigham and Women’s Hospital Communications

Altered microbiome, sleep deprivation, increase in alcohol consumption among possible culprits in 30-year global trend

A study by researchers from Brigham and Women’s Hospital reveals that the incidence of early onset cancers — including breast, colon, esophagus, kidney, liver, and pancreas — has dramatically increased around the world, with the rise beginning around 1990. In an effort to understand why many more people under 50 are being diagnosed with cancer, scientists conducted extensive analyses of available data, including information on early life exposures that might have contributed to the trend. Results are published in Nature Reviews Clinical Oncology.

“From our data, we observed something called the birth cohort effect. This effect shows that each successive group of people born at a later time — e.g., a decade later — have a higher risk of developing cancer later in life, likely due to risk factors they were exposed to at a young age,” said Shuji Ogino , a professor at Harvard Chan School and Harvard Medical School and a physician-scientist in the Department of Pathology at the Brigham. “We found that this risk is increasing with each generation. For instance, people born in 1960 experienced higher cancer risk before they turn 50 than people born in 1950, and we predict that this risk level will continue to climb in successive generations.”

Ogino worked with lead author Tomotaka Ugai and colleagues from 2000 to 2012 to analyze global data on 14 cancer types that showed increased incidence in adults before age 50. Then the team searched for available studies that examined trends of possible risk factors, including early life exposures in the general populations. Finally, the researchers examined the literature describing clinical and biological tumor characteristics of early onset cancers compared with cancers diagnosed after age 50.

“We found that this risk is increasing with each generation.” Shuji Ogino, professor, physician-scientist

In an extensive review, the team found that the early life “exposome,” which encompasses an individual’s diet, lifestyle, weight, environmental exposures, and microbiome, has changed substantially in the last several decades. They hypothesize that factors like the Western diet and lifestyle may be contributing to the rise in early onset cancer. The team acknowledged that this increased incidence of certain cancer types is, in part, due to early detection through cancer screening programs. They couldn’t precisely measure what proportion of this growing prevalence could solely be attributed to screening and early detection. However, they noted that increased incidence of many of the 14 cancer types is unlikely due to enhanced screening alone.

Possible risk factors for early onset cancer included alcohol consumption, sleep deprivation, smoking, obesity, and eating highly processed foods. Surprisingly, researchers found that while adult sleep duration hasn’t drastically changed over the several decades, children are getting far less sleep today than they were decades ago. Risk factors such as highly processed foods, sugary beverages, obesity, Type 2 diabetes, sedentary lifestyle, and alcohol consumption have all significantly increased since the 1950s.

“Among the 14 cancer types on the rise that we studied, eight were related to the digestive system. The food we eat feeds the microorganisms in our gut,” said Ugai. “Diet directly affects microbiome composition and eventually these changes can influence disease risk and outcomes.”

One limitation of this study is that researchers did not have an adequate amount of data from low- and middle-income countries to identify trends in cancer incidence over the decades. Going forward, Ogino and Ugai hope to continue this research by collecting more data and collaborating with international research institutes to better monitor global trends. They also explained the importance of conducting longitudinal cohort studies with parental consent to include young children who may be followed up for several decades.

“Without such studies, it’s difficult to identify what someone having cancer now did decades ago or when one was a child,” said Ugai. “Because of this challenge, we aim to run more longitudinal cohort studies in the future where we follow the same cohort of participants over the course of their lives, collecting health data, potentially from electronic health records, and biospecimens at set time points. This is not only more cost effective considering the many cancer types needed to be studied, but I believe it will yield us more accurate insights into cancer risk for generations to come.”

Ogino’s work is supported in part by the U.S. National Institutes of Health grants and the Cancer Research UK’s Cancer Grand Challenge Award. Ugai’s work is supported by grants from the Prevent Cancer Foundation, Japan Society for the Promotion of Science, and Mishima Kaiun Memorial Foundation.

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Cancer Researchers Begin Large Long-Term Study of Black Women

The American Cancer Society hopes to enroll 100,000 women and follow them for three decades to discover what’s causing higher case and death rates.

By Roni Caryn Rabin

The American Cancer Society has begun an ambitious, far-reaching study focusing on a population that has long been overlooked, despite high rates of cancer and cancer-related deaths: Black women.

The initiative, called VOICES of Black Women, is believed to be the first long-term population study of its size to zero in specifically on the factors driving cancer prevalence and deaths among Black women.

Researchers plan to enroll 100,000 Black women without cancer, ages 25 to 55, in Washington, D.C., and 20 states where most Black American women reside. The subjects will be surveyed twice a year about their behaviors, environmental exposures and life experiences, and followed for 30 years; any cancers they may develop will be tracked.

Similar studies by the American Cancer Society in the past yielded critical lessons about what causes cancer — for example, identifying cigarette smoking as a cause of lung cancer and linking red- and processed-meat consumption to increased risk of colon cancer.

While some earlier studies have included large numbers of Black women, the research wasn’t able to “hone in on the specific drivers of cancer in that population,” said Dr. Alpa Patel, senior vice president of population science at the society and co-principal investigator of the VOICES study, along with Dr. Lauren McCullough.

“In general population studies, you tend to ask questions that are going to be applicable to the majority of the population,” she said. “So going deeply into the lived experiences of discrimination, bias, systematic issues, environmental influences and cultural aspects of health-related behaviors, and how the narratives around them are shaped in different populations — those types of unique aspects of understanding what contributes to cancer in a population weren’t being asked about.”

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Cancer patients often do better with less intensive treatment, new research finds

FILE - In this May 25, 2017 file photo, chemotherapy drugs are administered to a patient at a hospital in Chapel Hill, N.C. Scaling back treatment in some cancers — ovarian, esophageal and Hodgkin lymphoma — can make life easier for patients without compromising outcomes, doctors reported at the American Society of Clinical Oncology annual meeting in early June 2024. (AP Photo/Gerry Broome, File)

• Copy Link copied

Scaling back treatment for three kinds of cancer can make life easier for patients without compromising outcomes, doctors reported at the world’s largest cancer conference.

It’s part of a long-term trend toward studying whether doing less — less surgery , less chemotherapy or less radiation — can help patients live longer and feel better. The latest studies involved ovarian and esophageal cancer and Hodgkin lymphoma.

Thirty years ago, cancer research was about doing more, not less. In one sobering example, women with advanced breast cancer were pushed to the brink of death with massive doses of chemotherapy and bone marrow transplants. The approach didn’t work any better than chemotherapy and patients suffered.

Now, in a quest to optimize cancer care, researchers are asking: “Do we need all that treatment that we have used in the past?”

It’s a question, “that should be asked over and over again,” said Dr. Tatjana Kolevska, medical director for the Kaiser Permanente National Cancer Excellence Program, who was not involved in the new research.

Often, doing less works because of improved drugs.

“The good news is that cancer treatment is not only becoming more effective, it’s becoming easier to tolerate and associated with less short-term and long-term complications,” said Dr. William G. Nelson of Johns Hopkins School of Medicine, who was also not involved in the new research.

Studies demonstrating the trend were discussed over the weekend at an American Society of Clinical Oncology conference in Chicago. Here are the highlights:

OVARIAN CANCER

French researchers found that it’s safe to avoid removing lymph nodes that appear healthy during surgery for advanced ovarian cancer. The study compared the results for 379 patients — half had their lymph nodes removed and half did not. After nine years, there was no difference in how long the patients lived and those with less-extreme surgery had fewer complications, such as the need for blood transfusions. The research was funded by the National Institute of Cancer in France.

ESOPHAGEAL CANCER

This German study looked at 438 people with a type of cancer of the esophagus that can be treated with surgery. Half received a common treatment plan that included chemotherapy and surgery on the esophagus, the tube that carries food from the throat to the stomach. Half got another approach that includes radiation too. Both techniques are considered standard. Which one patients get can depend on where they get treatment.

After three years, 57% of those who got chemo and surgery were alive, compared to 51% of those who got chemo, surgery and radiation. The German Research Foundation funded the study.

HODGKIN LYMPHOMA

A comparison of two chemotherapy regimens for advanced Hodgkin lymphoma found the less intensive treatment was more effective for the blood cancer and caused fewer side effects.

After four years, the less harsh chemo kept the disease in check in 94% of people, compared to 91% of those who had the more intense treatment. The trial included 1,482 people in nine countries — Germany, Austria, Switzerland, the Netherlands, Denmark, Sweden, Norway, Australia and New Zealand — and was funded by Takeda Oncology, the maker of one of the drugs used in the gentler chemo that was studied.

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Cancer at Nature Portfolio

The Nature Portfolio editors who handle cancer primary research, methods, protocols and reviews bring you the latest articles, covering all aspects from disease mechanisms to therapeutic approaches. Collected here you will also find specially curated content, such as collections, focus issues and animations, all ready to be used in presentations and educational materials. You can also find out about the editors handling cancer content, and the journals at Nature Portfolio that publish articles on this topic and how to submit to them.

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Research Articles

L-RNA aptamer-based CXCL12 inhibition combined with radiotherapy in newly-diagnosed glioblastoma: dose escalation of the phase I/II GLORIA trial

Recent studies show that targeting CXCL12 can improve the effect of radiotherapy (RT) in preclinical models of glioblastoma (GBM). Here, the authors report the safety and preliminary efficacy of a phase I/II clinical trial investigating an L-RNA aptamer-based CXCL12 inhibitor (NOX-A12) in combination with RT in patients with newly-diagnosed GBM.

• Frank A. Giordano
• Julian P. Layer
• Michael Hölzel

Circadian control of tumor immunosuppression affects efficacy of immune checkpoint blockade

Immunosuppression is regulated by the circadian clock and can be leveraged to promote the efficacy of immune checkpoint inhibitor therapy.

• Bridget M. Fortin
• Shannon M. Pfeiffer
• Selma Masri

Maintenance of R-loop structures by phosphorylated hTERT preserves genome integrity

Machitani, Nomura and colleagues report that hTERT suppresses R-loops through its RNA-dependent RNA polymerase activity and protects against genome instability.

• Mitsuhiro Machitani
• Akira Nomura
• Kenkichi Masutomi

C5aR1 inhibition reprograms tumor associated macrophages and reverses PARP inhibitor resistance in breast cancer

PARP inhibitors (PARPi) have been approved for the treatment of metastatic triple-negative breast cancer (BC), however resistance and recurrence are often observed. Here, in preclinical models of BRCA1/2 wild type and homologous recombination competent BC, the authors show that C5aR1-positive tumor associated macrophages are associated with PARPi-resistance, suggesting targeting C5aR1 as a therapeutic option.

• Alfonso Poire
• Gordon B. Mills

Glioblastoma disrupts cortical network activity at multiple spatial and temporal scales

The precise onset, temporal progression and spatial extent of neuron-tumor crosstalk in brain with Glioblastoma (GBM) are not fully understood. Here authors, using a genetic GBM mouse model, show widespread glutamate accumulation, chronic neural activity disruption between cells and brain areas, depending on tumor expansion rate and genotype with altered tumor and neural activity dynamics when adding glypican6.

• Jochen Meyer
• Jeffrey Noebels

Perinatal thymic-derived CD8αβ-expressing γδ T cells are innate IFN-γ producers that expand in IL-7R–STAT5B-driven neoplasms

Here the authors identify and characterize the development and function of an IFN-γ-producing CD8αβ + subset of γδ T cells that contributes to malignancy.

• Nital Sumaria
• Gina J. Fiala
• Bruno Silva-Santos

Proteomic analysis of the urothelial cancer landscape

Urothelial cancer is a challenging disease and an emerging field for targeted therapies. Here, the authors optimize clinical proteomics to provide proteome-level data on tumor specificity and identify robust prognostic subtypes with predictive information for repurposed drug candidates.

• Franz F. Dressler
• Falk Diedrichs
• Ákos Végvári

Deleting the mitochondrial respiration negative regulator MCJ enhances the efficacy of CD8 + T cell adoptive therapies in pre-clinical studies

Treatment failure following chimaeric antigen receptor (CAR) T cell therapy is common yet incompletely understood. In this study, the authors demonstrate that deletion of the mitochondrial negative regulator, MCJ, in CAR T cells promotes target cell killing ex vivo and augments their efficacy in an in vivo B cell leukaemia model.

• Meng-Han Wu
• Felipe Valenca-Pereira
• Mercedes Rincon

Immune features are associated with response to neoadjuvant chemo-immunotherapy for muscle-invasive bladder cancer

In the phase 2 study LCCC1520 (NCT02690558), clinical activity of pembrolizumab in combination with gemcitabine and cisplatin as neoadjuvant therapy in patients with muscle-invasive bladder cancer has been reported. Here the authors present molecular and immune cellular features associated with response to neoadjuvant chemo-immunotherapy.

• Wolfgang Beckabir
• Benjamin G. Vincent

HDAC activity is dispensable for repression of cell-cycle genes by DREAM and E2F:RB complexes

Here, the authors investigate the interplay among DREAM, RB, SIN3 proteins, and HDACs in the context of cell-cycle gene repression, suggesting that E2F:RB and DREAM complexes can repress cell-cycle genes without relying on HDAC activity.

• Alison K. Barrett
• Manisha R. Shingare
• Gerd A. Müller

H2AX promotes replication fork degradation and chemosensitivity in BRCA-deficient tumours

Histone H2AX has a known role in DNA damage repair but interestingly, its loss is associated with resistance to poly(ADP-ribose) polymerase (PARP) inhibition in BRCA-deficient tumours. Here, the authors identify a role of γH2AX in the degradation of replication forks and demonstrate that H2AX loss drives PARP inhibitor resistance via increased stressed fork stability in BRCA-deficient tumours.

• Diego Dibitetto
• Martin Liptay
• Sven Rottenberg

Prediction of recurrence risk in endometrial cancer with multimodal deep learning

A multimodal deep learning prognostic model based on histopathology outperforms current gold standards for identifying patients with endometrial cancer with different outcomes, in multiple external validation cohorts.

• Sarah Volinsky-Fremond
• Nanda Horeweg
• Tjalling Bosse

Single-cell and spatial transcriptomics analysis of non-small cell lung cancer

Myeloid cell populations play a critical role in lung cancer progression. Here, the authors use scRNA-seq and spatial transcriptomics to identify changes in the phenotype of macrophages within the tumour microenvironment.

• Marco De Zuani
• Haoliang Xue

Cadonilimab with chemotherapy in HER2-negative gastric or gastroesophageal junction adenocarcinoma: the phase 1b/2 COMPASSION-04 trial

In the COMPASSION-04 trial, first-line treatment with a bispecific antibody targeting CTLA-4 and PD-1 and chemotherapy in patients with locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma resulted in clinical responses with a manageable safety profile.

• Xiangyu Gao

Selective haematological cancer eradication with preserved haematopoiesis

An antibody–drug conjugate that targets the pan-haematopoietic marker CD45 combined with transplanted stem cells engineered to be shielded from it can eradicate leukaemic cells while preserving haematopoiesis.

• Simon Garaudé
• Romina Marone
• Lukas T. Jeker

Covalent targeted radioligands potentiate radionuclide therapy

Radiopharmaceuticals engineered with click chemistry to selectively bind to tumour-specific proteins can be used to successfully target tumour cells, boosting the pharmacokinetics of radionuclide therapy and improving tumour regression.

• Xi-Yang Cui

Drug screening on digital microfluidics for cancer precision medicine

In-vitro platforms for personalized cancer diagnosis is required high sensitivity. Here, the authors developed a digital microfluidic system for drug screening using primary tumor cells and established a working protocol for precision medicine.

• Yingying Liu

A whole-slide foundation model for digital pathology from real-world data

Prov-GigaPath, a whole-slide pathology foundation model pretrained on a large dataset containing around 1.3 billion pathology images, attains state-of-the-art performance in cancer classification and pathomics tasks.

• Naoto Usuyama
• Hoifung Poon

Engineering nanomaterials for glioblastoma nanovaccination

Developing vaccines for glioblastoma remains challenging owing to the immunosuppressive microenvironment of the tumour and the presence of the blood–brain barrier. In this Perspective, we explore how nanomaterials can be tailored to address the limitations of glioblastoma vaccination, potentially paving the way for important advancements.

• Fatima Hameedat
• Bárbara B. Mendes
• Flávia Sousa

Current understanding and management of CAR T cell-associated toxicities

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of various haematological malignancies but is associated with characteristic toxicities as well as less well-defined adverse effects, many of which can be severe and potentially fatal. The increasing clinical experience with CAR T cell products has resulted in better recognition and management of these toxicities using a range of pharmacotherapies, although this is an area of continued evolution and refinement. In this Review, Brudno and Kochenderfer discuss the current understanding and clinical management of CAR T cell-associated toxicities.

• Jennifer N. Brudno
• James N. Kochenderfer

Preclinical models of bladder cancer: BBN and beyond

In this Review, the authors comprehensively assess current models of bladder cancer with an emphasis on the N-butyl-N-(4-hydroxybutyl)-nitrosamine-induced bladder cancer model owing to its high fidelity to the human condition.

• David Matye
• Juliann Leak
• John A. Taylor III

Epidemiology of HPV-associated cancers past, present and future: towards prevention and elimination

Lessons from the prevention of cervical cancer, the first cancer type deemed amenable to elimination, can provide information on strategies to manage other cancers. Infection with human papillomavirus (HPV) causes virtually all cervical cancers and an important proportion of other cancer types. The authors of this Review discuss the epidemiology of HPV-associated cancers and the potential for their elimination, focusing on the cofactors that could have the greatest effect on prevention efforts and health equity.

• Talía Malagón
• Eduardo L. Franco
• Salvatore Vaccarella

AMPK as a mediator of tissue preservation: time for a shift in dogma?

This Review discusses the role of AMPK in cancer cachexia and metabolic dysfunction, including discussion of how targeting AMPK might be an option to preserve muscle and adipose tissue mass.

• Henning Tim Langer
• Lykke Sylow

A guide to artificial intelligence for cancer researchers

This Review provides an introductory guide to artificial intelligence (AI)-based tools for non-computational cancer researchers. Here, Perez-Lopez et al. outline the general principles of AI for image analysis, natural language processing and drug discovery, as well as how researchers can get started with each of them.

• Raquel Perez-Lopez
• Narmin Ghaffari Laleh
• Jakob Nikolas Kather

Mitochondrial function and gastrointestinal diseases

Mitochondria of the intestinal epithelium are vital in intestinal health and disease. This Review provides a comprehensive overview of intestinal epithelial cell mitochondrial dysfunction in inflammatory bowel diseases and colorectal cancer and discusses mitochondrial-targeted therapeutics for these diseases.

• Parsa S. Haque
• Neeraj Kapur
• Arianne L. Theiss

Centralization of care for rare genetic syndromes associated with cancer: improving outcomes and advancing research on VHL disease

In this Perspective, Larcher et al. describe a dedicated treatment programme for Von Hippel–Lindau disease established at San Raffaele Hospital, which encompasses diagnosis, surveillance, treatment, research and outreach. The authors then discuss the benefits of care centralization for Von Hippel–Lindau disease and other rare diseases.

• Alessandro Larcher
• Federico Belladelli
• Andrea Salonia

Targeted protein degradation: from mechanisms to clinic

This article reviews the current landscape of targeted protein degradation approaches and how they have parallels in biological processes. The authors also outline the ongoing clinical exploration of novel degraders and provide some perspectives on the directions the field might take.

• Jonathan M. Tsai
• Radosław P. Nowak
• Eric S. Fischer

From biology to the clinic — exploring liver metastasis in prostate cancer

In this Review, the authors provide a comprehensive overview of the epidemiological characteristics, prognosis, biological mechanisms, detection methods and treatment options for liver metastasis in prostate cancer. Guidance for future research directions in the field is also provided.

Engineering immune-evasive allogeneic cellular immunotherapies

Genome editing approaches can be used to confer immune-evasive properties to allogeneic cellular immunotherapies, with the aim of achieving persistent responses and efficiencies that are comparable to those of autologous chimeric antigen receptor T cell therapies. This Perspective discusses how current knowledge about viral or tumour immune evasion could be incorporated into the design of off-the-shelf tumour-specific T and NK cells for the production of cost-effective and scalable cancer immunotherapies.

• Karen E. Martin
• Quirin Hammer
• Karl-Johan Malmberg

Circadian regulation of cancer stem cells and the tumor microenvironment during metastasis

Barker and colleagues discuss the interplay between circadian rhythm, the tumor microenvironment and stem cells and how these are linked to metastasis as well as how these interactions could be clinically relevant.

• Rajesh Narasimamurthy
• Nick Barker

Unlocking ferroptosis in prostate cancer — the road to novel therapies and imaging markers

Ferroptosis induction is a promising new therapeutic strategy for advanced prostate cancer. In this Perspective, the authors discuss the interplay between ferroptosis and metabolism. Current efforts to target ferroptosis and combination therapies in prostate cancer, as well as emerging methods to monitor this process in patients, are also discussed.

• Pham Hong Anh Cao
• Abishai Dominic
• Elavarasan Subramani

Combinatorial strategies to target RAS-driven cancers

In this Review, Cichowski and colleagues provide an overview of combinatorial strategies designed to treat RAS-driven cancers that are based on four concepts that include vertical pathway inhibition, co-targeting RAS and adaptive survival pathways, co-targeting downstream or converging pathways and capitalizing on other cancer-associated vulnerabilities.

• Naiara Perurena
• Karen Cichowski

Lymphatic vessels in the age of cancer immunotherapy

Tumour-associated lymphatic growth and remodelling were once viewed as a passive means by which cancer cells could regionally spread to lymph nodes. However, recent data point to an active and contrasting role for lymphatic vessels and their transport in antitumour immune surveillance. In this Review, Karakousi et al. provide a working framework to define this role for the lymphatic system in tumour progression and present avenues for its therapeutic manipulation to improve cancer immunotherapy.

• Triantafyllia Karakousi
• Tenny Mudianto
• Amanda W. Lund

Antiangiogenic–immune-checkpoint inhibitor combinations: lessons from phase III clinical trials

The benefit of combining antiangiogenic agents with immune-checkpoint inhibitors has been demonstrated in pivotal phase III trials across different cancer types, some with practice-changing results; however, other phase III trials have had negative results. The authors of this Perspective discuss the variable outcomes of these trials, considering factors that account for these differences and suggesting future initiatives for improving the outcomes in patients receiving these combinations.

• Hung-Yang Kuo
• Kabir A. Khan
• Robert S. Kerbel

Nucleic acid-based drugs for patients with solid tumours

Nucleic acid-based therapies offer an alternative to traditional cancer treatment modalities, with promising data beginning to emerge. In this Review, the authors describe the design and development of nucleic acid-based therapies administered virally and non-virally, including discussions of the advantages and disadvantage of each approach, as well as the role of patient-specific factors such as the tumour microenvironment, and consider the most promising future research directions.

• Sebastian G. Huayamares
• David Loughrey
• Eric J. Sorscher

Hallmarks of sex bias in immuno-oncology: mechanisms and therapeutic implications

Sex differences impact various non-reproductive organ cancers, often leading to higher cancer incidence and poorer outcomes in male individuals. In this Perspective article, Xiao, Lee et al. outline the biological factors contributing to sex bias in immuno-oncology, emphasizing the need for future research to offer a fuller understanding of sex disparities in cancer.

The pleiotropic functions of reactive oxygen species in cancer

Papagiannakopoulos and colleagues discuss the roles of reactive oxygen species in cancer and the ways in which redox mechanisms may be exploited for cancer therapy.

• Katherine Wu
• Ahmed Ezat El Zowalaty
• Thales Papagiannakopoulos

Bone marrow inflammation in haematological malignancies

Haematological malignancies are associated with inflammation in the bone marrow. In this Review, the authors discuss how tumour-associated inflammation affects the normal functions of the bone marrow and supports the outgrowth and survival of malignant cells. Moreover, they describe how the inflammatory changes in the bone marrow differ in myeloid and lymphoid malignancies.

• Madelon M. E. de Jong
• Lanpeng Chen

Future direction of total neoadjuvant therapy for locally advanced rectal cancer

In this article, the authors discuss the use of total neoadjuvant therapy for locally advanced rectal cancer. They highlight ongoing trials and discuss future treatment options, including the potential use of multi-omics and artificial intelligence to facilitate treatment selection and prediction of response.

• Yoshinori Kagawa
• J. Joshua Smith
• Takayuki Yoshino

Targeting cuproplasia and cuproptosis in cancer

Copper is an essential trace element with inherent redox properties and fundamental roles in a diverse range of biological processes; therefore, maintaining copper homeostasis is crucial. In this Review, the authors discuss new insights into the mechanisms by which disrupted copper homeostasis contributes to tumour initiation and development, including the recently defined concepts of cuproplasia (copper-dependent cell growth and proliferation) and cuproptosis (a mitochondrial pathway of cell death triggered by excessive copper exposure). They also discuss potential strategies to exploit cuproplasia and cuproptosis for the treatment of cancer.

• Daolin Tang
• Guido Kroemer

Immunogenic cell death in cancer: targeting necroptosis to induce antitumour immunity

In this Review, Meier et al. discuss the molecular mechanisms of necroptosis, delineate how this form of immunogenic cell death activates antitumour immune responses and explore the opportunities and limitations of targeting necroptosis for anticancer therapy.

• Pascal Meier
• Arnaud J. Legrand

The present and future of bispecific antibodies for cancer therapy

Bispecific antibodies (bsAbs) can mediate therapeutic effects beyond those of natural monospecific antibodies. This Review provides an overview of recent developments in the field of bsAbs for cancer therapy and an outlook into next-generation bsAbs in earlier stages of development.

• Christian Klein
• Ulrich Brinkmann
• Roland E. Kontermann

Fungi in cancer

In this Viewpoint article, we asked three scientists working on the cancer mycobiome to provide their opinions on advancements and challenges and what the future holds for this exciting field of cancer research.

• Jessica Galloway-Peña
• Iliyan D. Iliev
• Florencia McAllister

News & Commentary

Adding ibrutinib to frontline therapy improves outcomes in transplant-eligible patients with mcl.

• David Killock

APOBEC3 upregulation drives gemcitabine resistance

Gemcitabine is a widely used chemotherapy drug that acts by targeting DNA replication. Understanding why many tumors are unresponsive to gemcitabine is a clinical challenge. A new study in Nature Cancer reports that upregulation of the cytidine deaminases APOBEC3C and APOBEC3D facilitates resistance to gemcitabine by protecting cells against DNA replication stress.

• John Maciejowski
• Taha Mohamed

Gaining ground in personalized breast cancer therapy: lesson learned from PHERGain

De-escalation of treatment for HER2 + breast cancer is a priority, given the increase in cure rates owing in part to improved HER2-targeted therapies. In this regard, the neoadjuvant approach provides the ideal platform to test less-intensive treatment regimens. Here we highlight a study that demonstrated the role of the metabolic response after dual HER2 blockade as a method of selecting patients who are most likely to benefit from chemotherapy-free neoadjuvant therapy.

• Maria Vittoria Dieci
• Valentina Guarneri

Polypeptide agonists of innate immune sensors

The physicochemical properties of cationic helical polypeptides can be optimized to induce endoplasmic reticulum stress in antigen-presenting cells so as to elicit antitumour innate immune responses.

• Michelle Z. Dion
• Natalie Artzi

Trapping the helicase

• Grant Miura

Predicting tumour origin with cytology-based deep learning: hype or hope?

The majority of patients with cancers of unknown primary have unfavourable outcomes when they receive empirical chemotherapy. The shift towards using precision medicine-based treatment strategies involves two options: tissue-agnostic or site-specific approaches. Here, we reflect on how cytology-based deep learning tools can be leveraged in these approaches.

• Nicholas Pavlidis

Fat, Desulfovibrio and cancer

This study by Chen et al. reveals that a high-fat diet leads to a predominance of Desulfovibrio species in the gut, correlating with a poor prognosis of breast cancer.

• Agustina Taglialegna

Overall survival with adjuvant pembrolizumab in renal cell carcinoma — the shock of the lightning

In the KEYNOTE-564 trial, patients with resected clear cell renal cell carcinoma at a high risk of relapse experienced disease-free survival and especially overall survival benefits following treatment with pembrolizumab, which in turn was established as the novel standard adjuvant therapy for these patients. Accurate patient selection is crucial. Managing post-pembrolizumab recurrence is challenging owing to limited evidence for guiding therapeutic decisions based on clinical features.

• Francesco Massari
• Matteo Rosellini
• Veronica Mollica

Taking a detour

Kong et al. have now shown that Knudson’s two-hit hypothesis can be circumvented through the actions of the glycolytic metabolite methylglyoxal, which transiently inactivates the tumour-suppressive functions of BRCA2 leading to episodic mutagenesis and cancer genome evolution.

Bone marrow stromal cells induce chromatin remodeling in multiple myeloma cells leading to transcriptional changes

Bone marrow stromal cells (BMSCs) are known to promote the development of drug resistance. Here, the authors investigate the chromatin remodeling and associated changes in gene expression in the multiple myeloma (MM) cells following their interactions with BMSCs, which are also observed in extramedullary disease (EMD).

• Moritz Binder
• Raphael E. Szalat
• Nikhil C. Munshi

Promoting the health of men of all backgrounds: educating ourselves to build trust and improve care

Specific issues affect the treatment of urological cancer and survivorship in gay and bisexual men. Creating an accepting and inclusive environment for these patients in our men’s health clinics can help to improve the quality of life for men from sexual minority groups undergoing cancer treatment.

• Danly Omil-Lima
• Austin Thompson
• Benjamin Crawshaw

Gut microbes linked to fatty diet drive tumour growth

Scientists know there is a link between obesity and some cancers. A study in mice and people suggests why that might be.

• Gillian Dohrn

Spatial and molecular exploration of glioblastoma heterogeneity

• Michael Fletcher

AUA24 — pioneering shared decision-making and patient engagement strategies

• Maria Chiara Masone

CAR T cells offer hope in glioblastoma

Novel CAR T cells delivered directly to the CNS could have therapeutic effects in recurrent glioblastoma, according to two early-stage trials.

A milestone method to make natural killer T cells

A differentiation protocol to produce off-the-shelf natural killer T cells may enable clinical application.

• Leonid S. Metelitsa

Refining neoadjuvant immunotherapy for resectable lung cancer

In an era of expanding perioperative approaches for resectable non–small-cell lung cancer, new data demonstrate that dual neoadjuvant immunotherapy targeting PD-1 and LAG-3 is feasible; future analyses may enhance patient selection by identifying immune signatures predictive of response.

• Misty D. Shields
• Christine M. Lovly

Overcoming barriers in cancer care for gender minorities

As the population of gender minorities grows in the setting of rising incidence of cancers globally, health-care professionals and institutions must be prepared to provide inclusive care. Individual-level training as well as institutional-level efforts on gender identity data collection and creation of inclusive clinical spaces could help mitigate health-care disparities.

• David J. Benjamin
• Omid Yazdanpanah
• Arash Rezazadeh Kalebasty

Right ON target: a new RAS-GTP inhibitor

Two studies published concurrently in Nature report the development and preclinical activity of RMC-7977, a multi-selective inhibitor targeting the active, GTP-bound form of RAS.

• Daniela Senft

New route to target RAS

• M. Teresa Villanueva

Studying paired patient tissue and blood enables insights into immunotherapy toxicity

Using single-cell RNA and T cell receptor sequencing along with microscopy, we identified the cell types and genes associated with immune checkpoint inhibitor therapy-related colitis. Our study will help to identify targets for early diagnosis and lays the groundwork for the development of safer immunotherapy regimens.

The annual American Association for Cancer Research (AACR) meeting provides a platform for scientists, clinicians and other stakeholders to share the latest advances in cancer science and medicine. Here, we outline some highlights of the 2024 meeting.

• Gabrielle Brewer

Dodging death

Ferroptosis, a cell death mechanism induced by lipid peroxidation, is pivotal in tumor suppression. A recent study shows that tumor repopulating cells evade ferroptosis and develop resistance to therapy via subverting a lipid metabolism enzyme.

• Yuelong Yan

Adjuvant pembrolizumab improves overall survival in patients with RCC

• Peter Sidaway

PRMT9 inhibition sparks immune responses in AML

Arginine methylation is crucial for tumor maintenance. PRMT9 levels are elevated in acute myeloid leukemia, and its inhibition eradicates leukemia by diminishing arginine methylation of proteins involved in DNA damage response and RNA translation. This activates the cGAS–STING pathway, which triggers immune responses directed against leukemia. Epigenetic targeting of DNA-damage-response mechanisms may bolster anti-tumor immunity.

• Antonella Santoro
• Raffaella Di Micco

Experimental evolution of cancer chromosomal changes

Experimental genome evolution of normal human cells reveals an intrinsic propensity to develop cancer-associated chromosomal alterations.

• Molly A. Guscott
• Sarah E. McClelland

Sarcoma ecotypes determine immunotherapy benefit

Sarcomas are heterogeneous connective tissue tumors that occur at various anatomic sites and are generally difficult to treat. Cell states in sarcoma ecosystems are now shown to be conserved across multiple subtypes and associated with response to immunotherapy and patient outcome.

• Johanna Wagner
• Stefan Fröhling

Adjuvant alectinib improves outcomes in ALK -mutant NSCLC

• Diana Romero

Methods & Protocols

Tutorial: design, production and testing of oncolytic viruses for cancer immunotherapy

This tutorial provides guidelines on oncolytic virus design, production and testing in cancer immunotherapy. Best practice recommendations for preclinical and clinical use of oncolytic viruses as an immunotherapy tool and related future challenges are also considered.

• Shashi Gujar
• Jonathan G. Pol
• John C. Bell

Engineering megabase-sized genomic deletions with MACHETE (Molecular Alteration of Chromosomes with Engineered Tandem Elements)

The authors introduce MACHETE (molecular alteration of chromosomes with engineered tandem elements), a clustered regularly interspaced short palindromic repeats directed Cas9-based system for the efficient deletion of megabase-sized genomic regions.

• Francisco M. Barriga
• Scott W. Lowe

CONIPHER: a computational framework for scalable phylogenetic reconstruction with error correction

CONIPHER is a computational framework for accurately inferring subclonal structure and the phylogenetic tree from multisample tumor sequencing, accounting for both copy number alterations and mutation errors.

• Kristiana Grigoriadis
• Ariana Huebner
• Nicholas McGranahan

Robust scoring of selective drug responses for patient-tailored therapy selection

This protocol presents a computational approach to scoring drug sensitivity that integrates multiple dose–response parameters into a single response metric and identifies differences in drug-response patterns between cancer cells and healthy control cells.

• Yingjia Chen
• Tero Aittokallio

INVADEseq to identify cell-adherent or invasive bacteria and the associated host transcriptome at single-cell-level resolution

Invasion–adhesion-directed expression sequencing adapts the 10x Genomics 5′ single-cell RNA sequencing protocol to enable generation of bacterial and eukaryotic DNA libraries to identify adherent or invasive bacteria and the associated host transcriptome at a single-cell level.

• Jorge Luis Galeano Niño
• Susan Bullman

Genome-wide pooled CRISPR screening in neurospheres

The authors present a protocol for genome-wide clustered regularly interspaced short palindromic repeat screening of three-dimensional neurospheres.

• Amy B. Goodale
• David E. Root

Newly diagnosed AML: quizartinib improves OS

Promising results for antisense RNA therapy in mouse models of diffuse midline glioma

• Caroline Barranco

Serum tumour markers for testicular cancer recurrence

The current serum tumour markers α-fetoprotein, human chorionic gonadotrophin, and lactate dehydrogenase show limited value for testicular cancer relapse detection. A recent study highlights that false-positive elevations in follow-up monitoring are common and, conversely, many patients do not have elevations despite proven relapse. These findings highlight the potential for circulating microRNAs to be used as improved biomarkers for relapse detection.

• Matthew J. Murray
• Cinzia G. Scarpini
• Nicholas Coleman

Stress response in tumor-infiltrating T cells is linked to immunotherapy resistance

A newly composed single-cell transcriptomic atlas of tumor-infiltrating T cells across 16 cancer types revealed previously undescribed T cell states and heterogeneity. A unique T cell stress response state, T STR , was linked to immunotherapy resistance. Our high-resolution T cell reference maps, web portal, and annotation tool can assist efforts to develop T cell therapies.

CD4 + CAR T cells — more than helpers

Therapeutic products containing CD8 + and CD4 + T cells expressing CARs are effective at inducing remission in patients with cancer. How CD4 + CAR T cells contribute to the anti-tumor response has not been well established. A study uses syngeneic models and in vivo imaging to glean mechanistic insights into how CD4 + T cells target tumors.

• M. Eric Kohler
• Terry J. Fry

Venetoclax–obinutuzumab combinations are effective in fit patients with CLL

Taking the temperature of lung cancer antigens

Antigen presentation is fundamental to anti-tumor immunity, but our understanding of the physiological and molecular inputs to the process in different contexts remains limited. Two new studies explore the contribution of cell-intrinsic proteolytic mechanisms and cell-extrinsic hot and cold tumor microenvironments in shaping the antigenic landscape in lung cancer.

• Paul A. Stewart
• Alex M. Jaeger

A skull bone marrow niche for antitumour neutrophils in glioblastoma

A preprint by Lad et al. shows that tumour-associated neutrophils in glioblastoma originate from skull bone marrow and acquire an antigen-presenting cell phenotype intratumorally in the presence of local T cells.

• Austeja Baleviciute

Impaired RNA clearance

In this study, Insco et al. find patient-specific CDK13 mutations to impede RNA surveillance, leading to the accumulation and translation of prematurely terminated RNAs that drive malignancy in melanoma models.

Peptide-mediated CRISPR engineering of cells

An article in Nature Biomedical Engineering reports a simple and hardware-independent peptide-mediated delivery method for the CRISPR-mediated engineering of T cells.

• Nesma El-Sayed Ibrahim

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Advances in Lung Cancer Research

Lung cancer cells driven by the KRAS oncogene, which is highlighted in purple.

NCI-funded researchers are working to advance our understanding of how to prevent, detect, and treat lung cancer. In particular, scientists have made progress in identifying many different genetic alterations that can drive lung cancer growth.

This page highlights some of the latest research in non-small cell lung cancer (NSCLC), the most common form of lung cancer, including clinical advances that may soon translate into improved care, NCI-supported programs that are fueling progress, and research findings from recent studies.

Early Detection of Lung Cancer

A great deal of research has been conducted in ways to find lung cancer early. Several methods are currently being studied to see if they decrease the risk of dying from lung cancer.

The NCI-sponsored  National Lung Screening Trial (NLST)  showed that low-dose CT scans can be used to screen for lung cancer in people with a history of heavy smoking. Using this screening can decrease their risk of dying from lung cancer. Now researchers are looking for ways to refine CT screening to better predict whether cancer is present. 

Markers in Blood and Sputum

Scientists are trying to develop or refine tests of sputum and blood that could be used to detect lung cancer early. Two active areas of research are:

• Analyzing blood samples to learn whether finding tumor cells or molecular markers in the blood will help diagnose lung cancer early.
• Examining sputum samples for the presence of abnormal cells or molecular markers that identify individuals who may need more follow-up.

Machine Learning

Machine learning is a method that allows computers to learn how to predict certain outcomes. In lung cancer, researchers are using computer algorithms to create computer-aided programs that are better able to identify cancer in CT scans than radiologists or pathologists. For example, in one artificial intelligence study , researchers trained a computer program to diagnose two types of lung cancer with 97% accuracy, as well as detect cancer-related genetic mutations.

Lung Cancer Treatment

Treatment options for lung cancer are surgery , radiation , chemotherapy , targeted therapy ,  immunotherapy , and combinations of these approaches. Researchers continue to look for new treatment options for all stages of lung cancer.

Treatments for early-stage lung cancer

Early-stage lung cancer can often be treated with surgery. Researchers are developing approaches to make surgery safer and more effective.

• When lung cancer is found early, people usually have surgery to remove an entire section ( lobe ) of the lung that contains the tumor. However, a recent clinical trial showed that, for certain people with early-stage NSCLC, removing a piece of the affected lobe is as effective as surgery to remove the whole lobe . 
• The targeted therapy  Osimertinib (Tagrisso ) was approved by the Food and Drug Administration (FDA) in 2021 to be given after surgery—that is, as adjuvant therapy —to people with early-stage NSCLC that has certain mutations in the EGFR gene.
• Two immunotherapy drugs, atezolizumab (Tecentriq)  and pembrolizumab (Keytruda) have been approved by the FDA to be used as adjuvant treatments after surgery and chemotherapy, for some patients with early-stage NSCLC. 
• The immunotherapy drug nivolumab (Opdivo) is approved to be used, together with chemotherapy, to treat patients with early-stage lung cancer before surgery (called neoadjuvant ). This approval, which came in 2022, was based on the results of the CheckMate 816 trial, which showed that patients at this stage who received neoadjuvant nivolumab plus chemotherapy lived longer than those who received chemotherapy alone . 
• In another trial (Keynote-671), patients with early-stage NSCLC who received pembrolizumab plus chemotherapy before surgery and pembrolizumab after surgery  had better outcomes than those who received just neoadjuvant or just adjuvant treatment.  

Treatments for advanced lung cancer

Newer therapies are available for people with advanced lung cancer. These primarily include immunotherapies and targeted therapies, which continue to show benefits as research evolves.  

Immunotherapy

Immunotherapies work with the body's immune system to help fight cancer. They are a major focus in lung cancer treatment research today. Clinical trials are ongoing to look at new combinations of immunotherapies with or without chemotherapy  to treat  lung cancer.

Immune checkpoint inhibitor s are drugs that block an interaction between proteins on immune cells and cancer cells which, in turn, lowers the immune response to the cancer. Several immune checkpoint inhibitors have been approved for advanced lung cancer, including  p embrolizumab (Keytruda) ,  a tezolizumab (Tecentriq) , c emiplimab (Libtayo) , d urvalumab (Imfinzi) , and  n ivolumab (Opdivo) .

A key issue with immunotherapies is deciding which patients are most likely to benefit. There is some evidence that patients whose tumor cells have high levels of an immune checkpoint protein called PD-L1 may be more responsive to immune checkpoint inhibitors. Another  marker for immunotherapy response is tumor mutational burden , or TMB, which refers to the amount of mutations in the DNA of the cancer cells. In some lung cancer trials, positive responses to immune checkpoint inhibitors have been linked with a high TMB. However, these markers cannot always predict a response and there is ongoing work to find better markers.

To learn more, see Immunotherapy to Treat Cancer .

Targeted Therapies

Targeted treatments identify and attack certain types of cancer cells with less harm to normal cells. In recent years, many targeted therapies have become available for advanced lung cancer and more are in development. Targeted treatments for lung cancer include the below.

Anaplastic lymphoma kinase (ALK) Inhibitors

ALK inhibitors target cancer-causing rearrangements in a protein called ALK. These drugs continue to be refined for the 5% of NSCLC patients who have an ALK gene alteration. Approved treatments include   ceritinib (Zykadia) , alectinib (Alecensa) , brigatinib   (Alunbrig) , and lorlatinib  (Lorbrena) .

These ALK inhibitors are improvements from previous ones in their enhanced ability to cross the blood–brain barrier. This progress is critical because, in non-small cell lung cancer patients with  ALK  alterations, disease progression tends to occur in the brain.   Based on clinical trial results, in 2024 the FDA approved alectinib as adjuvant therapy for people with ALK-positive NSCLC .

EGFR Inhibitors

• Lung Cancer Trial of Osimertinib Draws Praise—and Some Criticism

The drug improved survival in a large clinical trial, but some question the trial’s design.

EGFR inhibitors block the activity of a protein called epidermal growth factor receptor (EGFR). Altered forms of EGFR are found at high levels in some lung cancers, causing them to grow rapidly.  Osimertinib (Tagrisso) is the most effective and most widely used EGFR inhibitor. It is also used for adjuvant therapy after surgery for resectable NSCLC. Other drugs that target EGFR that are approved for treating NSCLC include afatinib (Gilotrif) , dacomitinib (Vizimpro) , erlotinib (Tarceva) , gefitinib (Iressa) . For people with Exon 20 mutations, amivantamab (Rybrevant)   is an approved targeted therapy.

ROS1 Inhibitors

The ROS1 protein is involved in cell signaling and cell growth. A small percentage of people with NSCLC have rearranged forms of the ROS1 gene. Crizotinib (Xalkori) and entrectinib (Rozlytrek) are approved as treatments for patients with these alterations. In late 2023, the FDA approved repotrectinib (Augtyro) for advanced or metastatic NSCLC with ROS1 fusions as an initial treatment and as a second-line treatment in those who previously received a ROS1-targeted drug.

BRAF Inhibitors

The B-Raf protein is involved in sending signals in cells and cell growth. Certain changes in the B-Raf gene can increase the growth and spread of NSCLC cells.

The combination of the B-Raf-targeted drug dabrafenib (Tafinlar)  and trametinib (Mekinist ), which targets a protein called MEK, has been approved as treatment for patients with NSCLC that has a specific mutation in the BRAF gene.

Encorafenib (Braftovi) combined with binimetinib (Mektovi) is approved for patients with metastatic NSCLC with a BRAF V600E mutation .

Other Inhibitors

Some NSCLCs have mutations in the genes NRTK-1 and NRTK-2 that can be treated with the targeted therapy larotrectinib (Vitrakvi). Those with certain mutations in the MET gene can be treated with tepotinib (Tepmetko) or capmatinib (Tabrecta) . And those with alterations in the RET gene are treated with selpercatinib (Retevmo)  and pralsetinib (Gavreto) . A 2023 clinical trial showed that treatment with selpercatinib led to longer progression-free survival compared with people who received chemotherapy with or without pembrolizumab. Inhibitors of other targets that drive some lung cancers are being tested in clinical trials.

See a complete list of  targeted therapies for lung cancer . 

NCI-Supported Research Programs

Many NCI-funded researchers at the NIH campus, and across the United States and the world, are seeking ways to address lung cancer more effectively. Some research is basic, exploring questions as diverse as the biological underpinnings of cancer and the social factors that affect cancer risk. And some is more clinical, seeking to translate basic information into improved patient outcomes. The programs listed below are a small sampling of NCI’s research efforts in lung cancer.

Pragmatica-Lung Study Enrolling Patients

The simplified trial may serve as a model for future cancer clinical trials.

• The Pragmatica-Lung Study is a randomized trial that will compare the combination of the targeted therapy ramucirumab (Cyramza) and the immunotherapy pembrolizumab (Keytruda) with standard chemotherapy in people with advanced NSCLC whose disease has progressed after previous treatment with immunotherapy and chemotherapy. In addition to looking at an important clinical question, the trial will serve as a model for future trials because it is designed to remove many of the barriers that prevent people from joining clinical trials.
• Begun in 2014, ALCHEMIST is a multicenter NCI trial for patients with early stage non-small cell lung cancer. It tests to see whether adding a targeted therapy after surgery, based on the genetics of a patient’s tumor, will improve survival.
• The Lung MAP trial is an ongoing multicenter trial for patients with advanced non-small cell lung cancer who have not responded to earlier treatment. Patients are assigned to specific targeted therapies based on their tumor’s genetic makeup.
• The Small Cell Lung Cancer Consortium  was created to coordinate efforts and provide a network for investigators who focus on preclinical studies of small-cell lung cancer. The goal of the consortium is to accelerate progress on this disease through information exchange, data sharing and analysis, and face-to-face meetings.
• NCI funds eight  lung cancer Specialized Programs of Research Excellence (Lung SPOREs) . These programs are designed to quickly move basic scientific findings into clinical settings. Each SPORE has multiple lung cancer projects underway.

Clinical Trials

NCI funds and oversees both early- and late-phase clinical trials to develop new treatments and improve patient care. Trials are available for both non-small cell lung cancer treatment  and small cell lung cancer treatment .

Lung Cancer Research Results

The following are some of our latest news articles on lung cancer research:

• Alectinib Approved as an Adjuvant Treatment for Lung Cancer
• Repotrectinib Expands Treatment Options for Lung Cancers with ROS1 Fusions
• Tarlatamab Shows Promise for Some People with Small Cell Lung Cancer
• Selpercatinib Slows Progression of RET-Positive Lung, Medullary Thyroid Cancers
• Lung-Sparing Surgery Is Effective for Some with Early-Stage Lung Cancer

View the full list of Lung Cancer Research Results and Study Updates .