research on cancer cure

12 new breakthroughs in the fight against cancer

Medical advances are continuing to help the world fight cancer. Image:  Unsplash/National Cancer Institute

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Madeleine north.

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This article was first published in May 2022, and most recently updated in October 2024 .

• Cancer is one of the world’s biggest killers, with around 10 million deaths per year due to the disease.
• Scientists working to improve the treatment and diagnosis of cancer are beginning to use AI, DNA sequencing and precision oncology among other techniques.
• A new trial giving cervical cancer patients a short course of chemotherapy before starting the standard treatment has cut the risk of death by 40%.
• The Centre for the Fourth Industrial Revolution India, a collaboration with the World Economic Forum, hopes to accelerate 18 cancer interventions.

Cancer kills around 10 million people a year and is a leading cause of death globally, according to the World Health Organization.

Breast, lung and colon cancer are among the most common. Death rates from cancer were falling before the pandemic . But COVID-19 caused a big backlog in diagnosis and treatment .

There is some good news, however. Medical advances are accelerating the battle against cancer. Here are 12 recent developments.

1. Personalized cancer vaccines

Thousands of NHS cancer patients in England could soon access trials of a new vaccine treatment. It's designed to prime the immune system to target cancer cells and reduce recurrence risk . These vaccines are also hoped to produce fewer side effects than conventional chemotherapy. Thirty hospitals have joined the Cancer Vaccine Launch Pad , which matches patients with upcoming trials using the same mRNA technology found in current COVID-19 jabs. Over 200 patients from the UK, Germany, Belgium, Spain and Sweden will receive up to 15 doses of the personalized vaccine, with the study expected to complete by 2027.

2. Test to identify 18 early-stage cancers

Researchers in the US have developed a test they say can identify 18 early-stage cancers. Instead of the usual invasive and costly methods, Novelna's test works by analyzing a patient's blood protein. In a screening of 440 people already diagnosed with cancer, the test correctly identified 93% of stage 1 cancers in men and 84% in women. The researchers believe the findings "pave the way for a cost-effective, highly accurate, multi-cancer screening test that can be implemented on a population-wide scale". It's early days, however. With such a small sample screening and a lack of information on co-existing conditions, the test is currently more of "a starting point for developing a new generation of screening tests for the early detection of cancer".

3. Seven-minute cancer treatment jab

England's National Health Service (NHS) is to be the first in the world to make use of a cancer treatment injection , which takes just seven minutes to administer, rather than the current time of up to an hour to have the same drug via intravenous infusion. This will not only speed up the treatment process for patients, but also free up time for medical professionals. The drug, Atezolizumab or Tecentriq, treats cancers including lung and breast, and it's expected most of the 3,600 NHS patients in England currently receiving it intravenously will now switch to the jab.

4. Precision oncology

Precision oncology is the “ best new weapon to defeat cancer ”, the chief executive of Genetron Health, Sizhen Wang, says in a blog for the World Economic Forum. This involves studying the genetic makeup and molecular characteristics of cancer tumours in individual patients. The precision oncology approach identifies changes in cells that might be causing the cancer to grow and spread. Personalized treatments can then be developed. The 100,000 Genomes Project, a National Health Service initiative, studied more than 13,000 tumour samples from UK cancer patients , successfully integrating genomic data to more accurately pin-point effective treatment. Because precision oncology treatments are targeted – as opposed to general treatments like chemotherapy – it can mean less harm to healthy cells and fewer side effects as a result.

5. Artificial intelligence fights cancer

In India, World Economic Forum partners are using emerging technologies like artificial intelligence (AI) and machine learning to transform cancer care. For example, AI-based risk profiling can help screen for common cancers like breast cancer, leading to early diagnosis. AI technology can also be used to analyse X-rays to identify cancers in places where imaging experts might not be available. These are two of 18 cancer interventions that the Centre for the Fourth Industrial Revolution India, a collaboration with the Forum , hopes to accelerate.

6. Greater prediction capabilities

Lung cancer kills more people in the US yearly than the next three deadliest cancers combined. It's notoriously hard to detect the early stages of the disease with X-rays and scans alone. However, MIT scientists have developed an AI learning model to predict a person's likelihood of developing lung cancer up to six years in advance via a low-dose CT scan. Trained using complex imaging data, 'Sybil' can forecast both short- and long-term lung cancer risk, according to a recent study. "We found that while we as humans couldn't quite see where the cancer was, the model could still have some predictive power as to which lung would eventually develop cancer," said co-author Jeremy Wohlwend.

7. Clues in the DNA of cancer

At Cambridge University Hospitals in England, the DNA of cancer tumours from 12,000 patients is revealing new clues about the causes of cancer, scientists say. By analyzing genomic data, oncologists are identifying different mutations that have contributed to each person’s cancer. For example, exposure to smoking or UV light, or internal malfunctions in cells. These are like “fingerprints in a crime scene”, the scientists say – and more of them are being found. “We uncovered 58 new mutational signatures and broadened our knowledge of cancer,” says study author Dr Andrea Degasperi, from Cambridge’s Department of Oncology.

8. Liquid and synthetic biopsies

Biopsies are the main way doctors diagnose cancer – but the process is invasive and involves removing a section of tissue from the body, sometimes surgically, so it can be examined in a laboratory. Liquid biopsies are an easier and less invasive solution where blood samples can be tested for signs of cancer. Synthetic biopsies are another innovation that can force cancer cells to reveal themselves during the earliest stages of the disease.

The application of “precision medicine” to save and improve lives relies on good-quality, easily-accessible data on everything from our DNA to lifestyle and environmental factors. The opposite to a one-size-fits-all healthcare system, it has vast, untapped potential to transform the treatment and prediction of rare diseases—and disease in general.

But there is no global governance framework for such data and no common data portal. This is a problem that contributes to the premature deaths of hundreds of millions of rare-disease patients worldwide.

The World Economic Forum’s Breaking Barriers to Health Data Governance initiative is focused on creating, testing and growing a framework to support effective and responsible access – across borders – to sensitive health data for the treatment and diagnosis of rare diseases.

The data will be shared via a “federated data system”: a decentralized approach that allows different institutions to access each other’s data without that data ever leaving the organization it originated from. This is done via an application programming interface and strikes a balance between simply pooling data (posing security concerns) and limiting access completely.

The project is a collaboration between entities in the UK (Genomics England), Australia (Australian Genomics Health Alliance), Canada (Genomics4RD), and the US (Intermountain Healthcare).

9. CAR-T-cell therapy

A treatment that makes immune cells hunt down and kill cancer cells was declared a success for leukaemia patients in 2022. Known as CAR-T-cell therapy, it involves removing and genetically altering immune cells, called T cells, from cancer patients. The altered cells then produce proteins called chimeric antigen receptors (CARs), which can recognize and destroy cancer cells. In the journal Nature , scientists at the University of Pennsylvania announced that two of the first people treated with CAR-T-cell therapy were still in remission 12 years on.

However, the US Food and Drug Administration is currently investigating whether the process can in fact cause cancer , after 33 cases of secondary cancer were observed in patients receiving CAR-T therapies. The jury is still out as to whether the therapy is to blame but, as a precaution, the drug packaging now carries a warning.

10. Fighting pancreatic cancer

Pancreatic cancer is one of the deadliest cancers. It is rarely diagnosed before it starts to spread and has a survival rate of less than 5% over five years. At the University of California San Diego School of Medicine, scientists developed a test that identified 95% of early pancreatic cancers in a study. The research, published in Nature Communications Medicine , explains how biomarkers in extracellular vesicles – particles that regulate communication between cells – were used to detect pancreatic, ovarian and bladder cancer at stages I and II.

Scientists are also getting closer to a cure. A new US/UK study has discovered that pancreatic cancer shuts down particular molecules in a key gene . The hope now is that the new knowledge "could lead to the development of more effective treatment options in the future ”, Dr Chris Macdonald, head of research at Pancreatic Cancer UK, told The Guardian.

Have you read?

Cancer: how to stop the next global health crisis, how to improve access to cancer medicines in low and middle-income countries, is digital health the next frontier in the global fight against cancer, 11. a tablet to cut breast cancer risk.

A drug that could halve the chance of women developing breast cancer is being tested out by England's National Health Service (NHS). It will be made available to almost 300,000 women seen as being at most risk of developing breast cancer, which is the most common type of cancer in the UK . The drug, named anastrozole, cuts the level of oestrogen women produce by blocking the enzyme aromatase . It has already been used for many years as a breast cancer treatment but has now been repurposed as a preventive medicine. “This is the first drug to be repurposed through a world-leading new programme to help us realize the full potential of existing medicines in new uses to save and improve more lives on the NHS," says NHS Chief Executive Amanda Pritchard.

12. Global cervical cancer treatment breakthrough

In October 2024, researchers announced the biggest breakthrough in cervical cancer treatment for two decades – in a trial at 32 medical centres in Brazil, India, Italy, Mexico, and the UK. Results from the INTERLACE trial showed that giving cervical cancer patients a short course of chemotherapy before starting the standard treatment reduced the risk of death 40%. It also reduced the risk of cervical cancer returning or growing again after responding to treatment by 35%. The two chemotherapy drugs used for the induction treatment are cheap, easily accessible and already approved for use, so they could become a new standard of care relatively quickly, according to the charity Cancer Research UK, which funded the research.

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Stanford University researchers have discovered a rapid and sustainable way to synthetically produce a promising cancer-fighting compound right in the lab. The compound’s availability has been limited because its only currently known natural source is a single plant species that grows solely in a small rainforest region of Northeastern Australia.

PhD students Edward Njoo, David Fanelli, Zach Gentry, and Owen McAteer. These researchers achieved the synthesis of the cancer-fighting compound EBC-46. (Image credit: Paul Wender)

The compound, designated EBC-46 and technically called tigilanol tiglate, works by promoting a localized immune response against tumors. The response breaks apart the tumor’s blood vessels and ultimately kills its cancerous cells. EBC-46 recently entered into human clinical trials following its extremely high success rate in treating a kind of cancer in dogs.

Given its complex structure, however, EBC-46 had appeared synthetically inaccessible, meaning no plausible path seemed to exist for producing it practically in a laboratory. However, thanks to a clever process, the Stanford researchers demonstrated for the first time how to chemically transform an abundant, plant-based starting material into EBC-46.

As a bonus, this process can produce EBC-46 “analogs” – compounds that are chemically similar, but which could prove even more effective and potentially treat a surprisingly wide range of other serious maladies. These diseases, which include AIDS, multiple sclerosis, and Alzheimer’s disease, all share biological pathways impacted by EBC-46’s target, a key enzyme called protein kinase C, or PKC.

“We are very excited to report the first scalable synthesis of EBC-46,” said Paul Wender , the Francis W. Bergstrom Professor in the School of Humanities and Sciences , professor of chemistry and, by courtesy, of chemical and systems biology at Stanford, and corresponding author of a study describing the results in the journal Nature Chemistry . “Being able to make EBC-46 in the lab really opens up tremendous research and clinical opportunities.”

Co-authors of the study are Zachary Gentry, David Fanelli, Owen McAteer, and Edward Njoo, all of whom are PhD students in Wender’s lab, along with former member Quang Luu-Nguyen.

Wender conveyed the immense satisfaction the research team felt over the EBC-46 synthesis breakthrough. “If you were to have visited the lab the first few weeks after they succeeded,” said Wender, “you would’ve seen my stellar colleagues smiling from ear to ear. They were able to do something many people had considered impossible.”

From a remote region

Tigilanol tiglate initially turned up through an automated drug candidate screening process by QBiotics, an Australian company. In nature, the compound appears in the seeds of the pink fruit of the blushwood tree, Fontainea picrosperma . Marsupials such as musky rat-kangaroos that eat blushwood fruit avoid the tigilanol tiglate-rich seeds, which when ingested trigger vomiting and diarrhea.

Injecting far smaller doses of EBC-46 directly into some solid tumors modifies the cellular signaling by PKC. Specifically, EBC-46 is proposed to activate certain forms of PKC, which in turn influence the activity of various proteins in the cancerous cells, attracting an immune response by the host’s body. The resulting inflammation makes the tumor’s vasculature, or blood vessels,  leaky, and this hemorrhaging causes the tumorous growth to die. In the case of external, cutaneous malignancies, the tumors scab up and fall off, and ways of delivering EBC-46 to internal tumors are being investigated.

In 2020, both the European Medicines Agency and the Food and Drug Administration in the United States approved an EBC-46–based medication, sold under the brand name Stelfonta, to treat mast cell cancer, the most common skin tumors in dogs. A study showed a 75% cure rate after a single injection and an 88% rate following a second dose. Clinical trials have since commenced for skin, head and neck, and soft tissue cancers in humans.

Based on these emerging research and clinical needs coupled with the source seeds’ geographical limitations, scientists have considered setting up special plantations for blushwood trees. But doing so presents a host of issues. For starters, the trees require pollination, meaning the right sort of pollinating animals must be on hand, plus trees must be planted in appropriate densities and distances to aid pollination. Furthermore, seasonal and climate variations affect the trees, along with pathogens. Setting aside plots for blushwood trees further poses land use problems.

“For sustainable, reliable production of EBC-46 in the quantities we need,” Wender said, “we really need to go the synthetic route.”

Making EBC-46 from scratch

A good starting point for making EBC-46, Wender and colleagues realized, is the plant-derived compound phorbol. More than 7,000 plant species produce phorbol derivatives worldwide and phorbol-rich seeds are commercially inexpensive. The researchers selected Croton tiglium , commonly known as purging croton, an herb used in traditional Chinese medicine.

The first step in preparing EBC-46, Wender explains, jibes with an everyday experience. “You buy a sack of these seeds, and it’s not unlike making coffee in the morning,” said Wender. “You grind up the seeds and run some hot solvent through them to extract the active ingredient,” in this case a phorbol-rich oil.

After processing the oil to yield phorbol, the researchers then had to figure out how to overcome the previously insurmountable challenge of bedecking a part of the molecule, called the B ring, with carefully placed oxygen atoms. This is required to enable EBC-46 to interact with PKC and modify the enzyme’s activity in cells.

To guide their chemical and biological studies, the researchers relied on instrumentation at the Stanford Neuroscience Microscopy Service, the Stanford Cancer Institute Proteomics/Mass Spectrometry Shared Resource, and the Stanford Sherlock cluster for computer modeling.

With this guidance, the team succeeded in adding extra oxygen atoms to phorbol’s B ring, first via a so-called ene (pronounced “een”) reaction conducted under flow conditions, where reactants mix as they run together through tubing. The team then introduced other B ring groups in a stepwise, controlled manner to obtain the desired spatial arrangements of the atoms. In total, only four to six steps were required to obtain analogs of EBC-46 and a dozen steps to reach EBC-46 itself.

Wender hopes that the far broader availability of EBC-46 and its PKC-influencing cousin compounds afforded by this breakthrough approach will accelerate research into potentially revolutionary new treatments.

“As we learn more and more about how cells function, we’re learning more about how we can control that functionality,” said Wender. “That control of functionality is particularly important in dealing with cells that go rogue in diseases ranging from cancer to Alzheimer’s.”

Wender is also a member of Stanford Bio-X and the Stanford Cancer Institute , and a fellow of  Sarafan ChEM-H .

To read all stories about Stanford science, subscribe to the biweekly Stanford Science Digest .

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Innovative approaches for cancer treatment: current perspectives and new challenges

Carlotta pucci, chiara martinelli, gianni ciofani.

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Correspondence to: Chiara Martinelli [email protected]

Received 2019 May 21; Collection date 2019.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Every year, cancer is responsible for millions of deaths worldwide and, even though much progress has been achieved in medicine, there are still many issues that must be addressed in order to improve cancer therapy. For this reason, oncological research is putting a lot of effort towards finding new and efficient therapies which can alleviate critical side effects caused by conventional treatments. Different technologies are currently under evaluation in clinical trials or have been already introduced into clinical practice. While nanomedicine is contributing to the development of biocompatible materials both for diagnostic and therapeutic purposes, bioengineering of extracellular vesicles and cells derived from patients has allowed designing ad hoc systems and univocal targeting strategies. In this review, we will provide an in-depth analysis of the most innovative advances in basic and applied cancer research.

Keywords: cancer, nanomedicine, extracellular vesicles, targeted therapy, immunotherapy, gene therapy, thermal ablation, radiomics, pathomics

Introduction

Cancer is one of the main causes of death worldwide, and in the past decade, many research studies have focused on finding new therapies to reduce the side effects caused by conventional therapies.

During cancer progression, tumours become highly heterogeneous, creating a mixed population of cells characterised by different molecular features and diverse responsivity to therapies. This heterogeneity can be appreciated both at spatial and temporal levels and is the key factor responsible for the development of resistant phenotypes promoted by a selective pressure upon treatment administration [ 1 ]. Usually, cancer is treated as a global and homogeneous disease and tumours are considered as a whole population of cells. Thus, a deep understanding of these complex phenomena is of fundamental importance in order to design precise and efficient therapies.

Nanomedicine offers a versatile platform of biocompatible and biodegradable systems that are able to deliver conventional chemotherapeutic drugs in vivo , increasing their bioavailability and concentration around tumour tissues, and improving their release profile [ 2 ]. Nanoparticles can be exploited for different applications, ranging from diagnosis to therapy [ 2 ].

Recently, extracellular vesicles (EVs), responsible for cancer development, microenvironment modification and required for metastatic progression, have been widely investigated as efficient drug delivery vehicles [ 3 ].

Natural antioxidants and many phytochemicals have been recently introduced as anti-cancer adjuvant therapies due to their anti-proliferative and pro-apoptotic properties [ 4 , 5 ].

Targeted therapy is another branch of cancer therapy aiming at targeting a specific site, such as tumour vasculature or intracellular organelles, leaving the surroundings unaffected. This enormously increases the specificity of the treatment, reducing its drawbacks [ 6 ].

Another promising opportunity relies on gene therapy and expression of genes triggering apoptosis [ 7 ] and wild type tumour suppressors [ 8 ], or the targeted silencing mediated by siRNAs, currently under evaluation in many clinical trials worldwide [ 9 ].

Thermal ablation of tumours and magnetic hyperthermia are opening new opportunities for precision medicine, making the treatment localised in very narrow and precise areas. These methods could be a potential substitute for more invasive practices, such as surgery [ 10 , 11 ].

Furthermore, new fields such as radiomics and pathomics are contributing to the development of innovative approaches for collecting big amounts of data and elaborate new therapeutic strategies [ 12 , 13 ] and predict accurate responses, clinical outcome and cancer recurrence [ 14 – 16 ].

Taken all together, these strategies will be able to provide the best personalised therapies for cancer patients, highlighting the importance of combining multiple disciplines to get the best outcome.

In this review, we will provide a general overview of the most advanced basic and applied cancer therapies, as well as newly proposed methods that are currently under investigation at the research stage that should overcome the limitation of conventional therapies; different approaches to cancer diagnosis and therapy and their current status in the clinical context will be discussed, underlining their impact as innovative anti-cancer strategies.

Nanomedicine

Nanoparticles are small systems (1–1,000 nm in size) with peculiar physicochemical properties due to their size and high surface-to-volume ratio [ 17 ]. Biocompatible nanoparticles are used in cancer medicine to overcome some of the issues related to conventional therapies, such as the low specificity and bioavailability of drugs or contrast agents [ 2 ]. Therefore, encapsulation of the active agents in nanoparticles will increase their solubility/biocompatibility, their stability in bodily fluids and retention time in the tumour vasculature [ 18 – 20 ]. Furthermore, nanoparticles can be engineered to be extremely selective for a precise target [ 21 , 22 ] (see the “Targeted therapy and immunotherapy” section) and to release the drug in a controlled way by responding to a specific stimulus [ 18 , 23 – 25 ]. This is the case of ThermoDox, a liposomal formulation that can release doxorubicin as a response to an increment of temperature [ 26 ].

Inorganic nanoparticles are generally used as contrast agents for diagnosis purposes. Among them, quantum dots are small light-emitting semiconductor nanocrystals with peculiar electronic and optical properties, which make them highly fluorescent, resistant to photobleaching and sensitive for detection and imaging purposes [ 27 ]. Combined with active ingredients, they can be promising tools for theranostic applications [ 27 ]. In a recent study, quantum dots coated with poly(ethylene glycol) (PEG) were conjugated to anti-HER2 antibody and localised in specific tumour cells [ 28 ].

Superparamagnetic iron oxide nanoparticles (SPIONs) are usually exploited as contrast agents in magnetic resonance imaging (MRI) because they interact with magnetic fields [ 29 , 30 ]. Five types of SPIONs have been tested for MRI: ferumoxides (Feridex in the US, Endorem in Europe), ferucarbotran (Resovist), ferucarbotran C (Supravist, SHU 555 C), ferumoxtran-10 (Combidex) and NC100150 (Clariscan). Ferucarbotran is currently available in few countries, while the others have been removed from the market [ 25 ]. SPIONs have also been studied for cancer treatment by magnetic hyperthermia (see the “Thermal ablation and magnetic hyperthermia” section), and a formulation of iron oxide coated with aminosilane called Nanotherm has been already approved for the treatment of glioblastoma [ 31 ].

Gold nanoparticles have raised interest because of their optical and electrical properties and low toxicity [ 32 – 34 ]. They are mainly used as contrast agents for X-ray imaging, computed tomography [ 25 ], photoacoustic imaging [ 35 ] and photodynamic therapy [ 36 ]. A nanoshell made of a silica core and a gold shell coated with PEG was approved by the Food and Drug Administration (FDA) in 2012 and commercialised as AuroShell (Nanospectra) for the treatment of breast cancer by photodynamic therapy [ 25 ].

Organic nanoparticles are mainly used as delivery systems for drugs. Liposomes and micelles are both made of phospholipids, but they differ in their morphology. Liposomes are spherical particles having at least one lipid bilayer, resembling the structure of cell membranes. They are mainly used to encapsulate hydrophilic drugs in their aqueous core, but hydrophobic drugs can also be accommodated in the bilayer or chemically attached to the particles [ 37 ]. Micelles, instead, own a hydrophobic core that can encapsulate hydrophobic drugs [ 38 ]. Doxil, doxorubicin-loaded PEGylated liposomes, were the first nanoparticles approved by the FDA in 1995 to treat AIDS-associated Kaposi’s sarcoma [ 39 ]. This formulation drastically reduces doxorubicin side effects. Since then, other liposomal formulations have been approved by the FDA for cancer therapy, such as Myocet and DaunoXome [ 40 – 42 ]. Polymeric nanoparticles are made of biocompatible or natural polymers, such as poly(lactide-co-glycolide), poly(ε-caprolactone), chitosan, alginate and albumin [ 43 ]. Some formulations have already been accepted by the FDA, such as Abraxane (albumin-paclitaxel particles for the treatment of metastatic breast cancer and pancreatic ductal adenocarcinoma) and Ontak (an engineered protein combining interleukin-2 and diphtheria toxins for the treatment of non-Hodgkin’s peripheral T-cell lymphomas).

As well as these systems, which have been either accepted or are under clinical investigation, it is worth mentioning some new nanoparticles currently undergoing testing at the research level, which should improve treatment performance. For example, solid lipid nanoparticles, made of lipids that are solid at body temperature [ 44 ], and fabricated to load hydrophobic drugs [ 45 ] have been demonstrated to give a higher drug stability and prolonged release compared to other systems; however, the encapsulation efficiency is often low because of their high crystallinity [ 46 ]. To overcome this issue, one or more lipids, liquid at room temperature (like oleic acid, for example), are included in the formulation [ 47 ]. Lipid nanoparticles are good candidates for brain tumour therapy as they are able to cross the blood–brain barrier (BBB) [ 48 ]. A recent work showed that lipid nanoparticles loaded with SPIONs and temozolomide are efficient to treat glioblastoma since they combine the effect of the conventional chemotherapy and hyperthermia [ 49 , 50 ]. Dendrimers are another family of nanoparticles composed of polymers with a repetitive branched structure and characterised by a globular morphology [ 51 , 52 ]. Their architecture can be easily controlled, making their structure extremely versatile for many applications. For example, some recent studies show that poly-L-lysine (PLL) dendrimers loaded with doxorubicin induce anti-angiogenic responses in in vivo tumour models [ 53 ]. Currently, there is only one clinical trial for a formulation named ImDendrim based on a dendrimer and on a rhenium complex coupled to an imidazolium ligand, for the treatment of inoperable liver cancers that do not respond to conventional therapies [ 54 ].

Extracellular vesicles for cancer diagnosis and therapy

EVs are classified in two categories based on their biogenesis. Specifically, exosomes are small vesicles of around 30–150 nm originated from endosomes in physiological and pathological conditions and released by a fusion of multivesicular bodies (MVBs) to the cell membrane [ 55 , 56 ], while shed microvesicles (sMVs), with a typical size of 50–1,300 nm, are present in almost any extracellular bodily fluid and are responsible for the exchange of molecular materials between cells [ 57 , 58 ]. Exosomes are involved in cancer development and spreading [ 3 , 59 , 60 ], in the bidirectional communication between tumour cells and surrounding tissues, and in the construction of the microenvironment needed for pre-metastatic niche establishment and metastatic progression [ 61 ]. Hence, circulating vesicles are clinically relevant in cancer diagnosis, prognosis and follow up. Exosomes are actually recognised as valid diagnostic tools, but they can also be isolated and exploited as anti-cancer vaccines or nanosized drug carriers in cancer therapy [ 62 ].

Nowadays, one of the main issues in cancer diagnosis is the early identification of biomarkers by non-invasive techniques. Obtaining a significant amount of information, before and during tumour treatment, should allow the monitoring of cancer progression and the efficacy of therapeutic regimens. Liquid biopsies to detect circulating tumour cells, RNAs, DNAs and exosomes have been used as indicators for personalised medicine [ 63 ]. In recent years, exosomes detection has been validated as a reliable tool for preclinical practice in different cancer types [ 64 ], thanks to the identification of their content: double-stranded DNA (dsDNA) [ 65 , 66 ], messenger RNA (mRNA), micro RNA (miRNA), long non-coding RNA (lncRNA) [ 67 ], proteins and lipids [ 68 ]. DsDNA has been detected in exosomes isolated from plasma and serum of different cancer cell types, and mutated genes involved in tumorigenesis, such as mutated KRAS and TP53 [ 69 , 70 ], have been identified as disease predictors. Similarly, exosomal AR-V7 mRNA has been used as a prognostic marker of resistance to hormonal therapy in metastatic prostate cancer patients [ 71 ]. Gene expression profiling of multiple RNAs from urinary exosomes has been adopted as an efficient diagnostic tool [ 72 ]. LncRNAs isolated from serum exosomes have been exploited for disease prognosis in colorectal cancer patients [ 73 ], and multiple miRNAs allow one to distinguish between different lung cancer subtypes [ 74 ]. GPC1-positive exosomes have been employed to detect pancreatic cancer [ 75 ], while circulating exosomal macrophage migration inhibitory factor (MIF) was able to predict liver metastasis onset [ 76 ]. Finally, multiple lipids present in urinary exosomes have been approved as prostate cancer indicators [ 77 ]. Due to the high variability of patient classes and sample size, and in order to obtain clinically significant results for a fast and effective diagnosis, huge investments in exosome research will be required in the near future.

Exosomes could also be exploited as natural, biocompatible and low immunogenic nanocarriers for drug delivery in cancer therapy. They can be passively loaded by mixing purified vesicles with small drugs [ 78 – 82 ], or actively loaded by means of laboratory techniques, such as electroporation and sonication [ 83 , 84 ]. Superparamagnetic nanoparticles conjugated to transferrin have been tested for the isolation of exosomes expressing transferrin receptor from mice blood. After incubation with doxorubicin, they have been used to target liver cancer cells in response to external magnetic fields, inhibiting cell growth both in vitro and in vivo [ 80 ]. Kim et al. [ 83 ] engineered mouse macrophage-derived exosomes with aminoethyl anisamide-PEG to target sigma receptor, overexpressed in lung cancer cells and passively loaded them with paclitaxel. These systems acted as targeting agents able to suppress metastatic growth in vivo .

Three clinical trials with loaded exosomes are currently ongoing for the treatment of different tumours [ 85 – 87 ]: a phase I trial is evaluating the ability of exosomes to deliver curcumin to normal and colon cancer tissues [ 85 ]; a phase II trial is investigating the in vivo performance of autologous tumour cell-derived microparticles carrying methotrexate in lung cancer patients [ 86 ] and a clinical inquiry is focusing on autologous erythrocyte-derived microparticles loaded with methotrexate for gastric, colorectal and ovarian cancer treatment [ 87 ].

Recently, new strategies to produce ad hoc exosomes have been developed. Cells releasing exosomes have been genetically engineered to overexpress specific macromolecules, or modified to release exosomes with particular targeting molecules [ 88 – 90 ].

Exosomes derived from different cancer cells have already been exploited as cancer vaccines. Autologous dendritic cell-derived exosomes with improved immunostimulatory function have been tested in a phase II clinical trial for the activation of CD8 + T cells [ 91 ] in non-small cell lung cancer (NSCLC) patients, observing disease stabilisation and a better overall survival [ 92 ]. In a phase I trial, ascites-derived exosomes supplemented with granulocyte-macrophage colony stimulating factor (GM-CSF) have been administered to colorectal cancer patients, soliciting a tumour-specific immune response [ 93 ].

Many issues related to exosomes clinical translation remain open and are mostly connected to the definition of preclinical procedures for isolation, quantification, storage and standard protocols for drug loading. It is becoming even more necessary to distinguish between tumour and healthy blood cell-derived vesicles to characterise their post-isolation half-life and to perform standard content analyses. For these purposes, innovative approaches and technologies have been set up, such as microarrays and specific monoclonal antibodies and RNA markers amplification strategies [ 94 ].

Natural antioxidants in cancer therapy

Every day, the human body undergoes several exogenous insults, such as ultraviolet (UV) rays, air pollution and tobacco smoke, which result in the production of reactive species, especially oxidants and free radicals, responsible for the onset of many diseases, including cancer. These molecules can also be produced as a consequence of clinical administration of drugs, but they are also naturally created inside our cells and tissues by mitochondria and peroxisomes, and from macrophages metabolism, during normal physiological aerobic processes.

Oxidative stress and radical oxygen species are able to damage DNA (genetic alterations, DNA double strand breaks and chromosomal aberrations [ 95 , 96 ]) and other bio-macromolecules [ 97 ], such as lipids (membrane peroxidation and necrosis [ 98 ]) and proteins (significantly changing the regulation of transcription factors and, as a consequence, of essential metabolic pathways [ 99 ]).

The protective mechanisms our body has developed against these molecules are sometimes insufficient to counteract the huge damages produced. Recently, in addition to research into the roles of the physiological enzymes superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GP), natural antioxidants such as vitamins, polyphenols and plant-derived bioactive compounds are being studied in order to introduce them as preventive agents and potential therapeutic drugs [ 100 , 101 ]. These molecules have anti-inflammatory and anti-oxidant properties and are found in many vegetables and spices [ 102 ]. Vitamins, alkaloids, flavonoids, carotenoids, curcumin, berberine, quercetin and many other compounds have been screened in vitro and tested in vivo , displaying appreciable anti-proliferative and pro-apoptotic properties, and have been introduced as complementary therapies for cancer [ 4 , 5 , 103 ].

Despite the advantages of using natural drugs, their translation into clinical practice remains difficult due to their limited bioavailability and/or toxicity. Curcumin, a polyphenolic compound extracted from turmeric ( Curcuma longa ), is a traditional Southeast Asian remedy with anti-inflammatory, anti-oxidant and chemopreventive and therapeutic activities [ 104 ]. It has been shown to have cytotoxic effects in different kinds of tumours, such as brain, lung, leukaemia, pancreatic and hepatocellular carcinoma [ 105 , 106 ], with no adverse effects in normal cells at the effective therapeutic doses [ 107 ]. Curcumin can modulate a plethora of cellular mechanisms [ 108 , 109 ]; however, its biological properties, and as a consequence, the treatment duration and the efficient therapeutic doses, have not been completely elucidated yet. This molecule is highly lipophilic, poorly soluble in water and not very stable [ 110 ]. Different strategies and specific carriers, such as liposomes and micelles [ 111 , 112 ], have been developed to improve its bioavailability. Currently, 24 clinical trials involving curcumin are ongoing and 23 have been already completed [ 113 ].

Berberine is an alkaloid compound extracted from different plants, such as Berberis . Recently, it has been demonstrated to be effective against different tumours and to act as a chemopreventive agent, modulating many signalling pathways [ 114 , 115 ]. Like curcumin, it is poorly soluble in water; therefore, different nanotechnological strategies have been developed to facilitate its delivery across cell membranes [ 116 – 119 ]; six clinical trials are open and one has been completed [ 120 ].

Quercetin, a polyphenolic flavonoid found in fruits and vegetable, has been proven to be effective to treat several tumours, such as lung, prostate, liver, colon and breast cancers [ 121 – 123 ], by binding cellular receptors and interfering with many signalling pathways [ 124 ]. Interestingly, it has been shown to be effective also in combination with chemotherapeutic agents [ 125 ]. Presently, seven clinical trials are open and four have been completed [ 126 ].

Targeted therapy and immunotherapy

One of the main problems of conventional cancer therapy is the low specificity of chemotherapeutic drugs for cancer cells. In fact, most drugs act both on healthy and diseased tissues, generating severe side effects. Researchers are putting a lot of effort into finding a way to target only the desired site. Nanoparticles have raised great interest for their tendency to accumulate more in tumour tissues due to the enhanced permeability and retention effect (EPR) [ 127 ]. This process, called passive targeting, relies on the small size of nanoparticles and the leaky vasculature and impaired lymphatic drainage of neoplastic tissues [ 6 ]. Passive targeting, however, is difficult to control and can induce multidrug resistance (MDR) [ 128 ]. Active targeting, on the other hand, enhances the uptake by tumour cells by targeting specific receptors that are overexpressed on them [ 129 , 130 ]. Nanoparticles, for example, can be functionalized with ligands that univocally bind particular cells or subcellular sites [ 6 ]. Several kinds of ligands can be used, such as small molecules, peptides, proteins, aptamers and antibodies.

Folic acid and biotin are small molecules, whose receptors are overexpressed in tumour tissues. Several nanocarriers have been functionalized with folic acid to target ovarian and endometrial cancers [ 131 ]: folic acid-conjugated polyethylene glycol-poly(lactic-co-glycolic acid) nanoparticles delivering docetaxel increased drug cellular uptake by human cervical carcinoma cells [ 132 ]. Small ligands are cheap and can be linked to nanoparticles by simple conjugation chemistry [ 133 , 134 ].

Different kinds of small peptides and proteins are also effective in active targeting. Angiopep-2 is a peptide that has raised great interest in the treatment of brain cancer [ 135 ], because it binds to low-density lipoprotein receptor-related protein-1 (LRP1) of endothelial cells in the BBB, and it is also overexpressed in glioblastoma cancer cells [ 136 ]. Bombesin peptide conjugated to poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with docetaxel was used to target the gastrin-releasing peptide receptor, overexpressed on cell surface of prostate, breast, ovarian, pancreatic and colorectal cancer cells [ 137 , 138 ]. Transferrin is a serum glycoprotein overexpressed on many solid tumours, especially on glioblastoma multiforme cells [ 139 ], and on epithelial cells of the BBB [ 6 , 140 ]. Transferrin-conjugated chitosan-PEG nanoparticles delivering paclitaxel exhibited a higher cytotoxicity towards transferrin-overexpressing human non-small cell lung cancer cells (NSCLCs) (HOP-62) [ 141 ].

Aptamers are small synthetic single-stranded RNA or DNA oligonucleotides folded into specific shapes that make them capable of binding specific targets [ 142 ]. Farokhzad et al. [ 143 ] reported that the use of A10 RNA aptamer conjugated to docetaxel-loaded nanoparticles significantly enhances in vitro cytotoxicity. The same aptamer has been also used to prepare quantum dot-doxorubicin conjugates [ 144 ].

Antibodies are currently the most exploited ligands for active targeting. These proteins have a typical ‘Y’ shape, where the two arms are responsible for the selective interaction with the antigen [ 145 ]. Antibodies can be used as immunoconjugates, when conjugated to a drug or nanoparticle, or naked. In the first case, their function is mainly to target a specific antigen overexpressed on cancer cells. Antibodies used for this purpose include those ones that bind to the human epidermal growth factor receptor 2 (HER2), the epidermal growth factor receptor (EGFR), the transferrin receptor (TfR) and the prostate-specific membrane antigen (PSMA) [ 6 ]. Rapamycin-PLGA nanoparticle conjugated to EGFR antibody exhibited higher cellular uptake by human breast adenocarcinoma cells (MCF-7), with enhanced apoptotic activity [ 146 ]. Loperamide-loaded human serum albumin nanoparticles conjugated to antibodies that specifically bind transferrin receptor successfully crossed the BBB and delivered the drug to the desired site [ 147 ].

Naked antibodies or immunoconjugates can also be used in immunotherapy, which is a cancer treatment that aims at stimulating or restoring the immune system of the patient against cancer cells [ 148 ]. Antibodies can act as markers for cancer cells to make them more vulnerable to the immune system response (non-specific immune stimulation), or as inhibitors for immune checkpoint proteins on cancer cell surface, that can modulate the action of T-cells [ 148 ]. Several antibodies have been already tested and accepted by FDA for immunotherapy, such as rituximab (1997, [ 149 ]), ibritumomab tiuxetan (2002, [ 150 ]), trastuzumab emtansine (2013, [ 151 ]), nivolumab (2014, [ 152 ]) and pembrolizumab (2014, [ 153 ]).

Immunotherapy can be achieved by another strategy called adoptive cell transfer (ACT) and it consists of isolating T-lymphocytes (T-cells) with the highest activity against cancer directly from the patient’s blood, expanding them ex vivo , and reinfusing them again into the patient [ 154 ]. Autologous T-cells can be genetically engineered in vitro to express a chimaeric antigen receptor (CAR), which makes them more specific against cancer cell antigens [ 148 ]. Different CARs can be designed to be directed against a certain cancer antigen. The genetic modification of T-cells can be achieved by different methods such as viral transduction, non-viral methods like DNA-based transposons, CRISPR/Cas9 or other plasmid DNA and mRNA transfer techniques (i.e., electroporation, encapsulation in nanoparticles) [ 155 ]. ACT protocols have been already adopted in clinical practice for advanced or recurrent acute lymphoblastic leukaemia and for some aggressive forms of non-Hodgkin’s lymphoma [ 148 ]. For example, it has been shown that the treatment of end-stage patients affected by acute lymphocytic leukaemia with CAR T-cells led to a full recovery in up to 92% of patients [ 155 ]. Despite these very promising results, much research is currently devoted to understanding the long-term side effects of CAR T-cell therapies and their fate within tumours, and to improving CAR T-cell expansion technologies.

Gene therapy for cancer treatment

Gene therapy is intended as the introduction of a normal copy of a defective gene in the genome in order to cure specific diseases [ 156 ]. The first application dates back to 1990 when a retroviral vector was exploited to deliver the adenosine deaminase (ADA) gene to T-cells in patients with severe combined immunodeficiency (SCID) [ 157 ]. Further research demonstrated that gene therapy could be applied in many human rare and chronic disorders and, most importantly, in cancer treatment. Approximately 2,900 gene therapy clinical trials are currently ongoing, 66.6% of which are related to cancer [ 158 ]. Different strategies are under evaluation for cancer gene therapy: 1) expression of pro-apoptotic [ 159 , 160 ] and chemo-sensitising genes [ 4 ]; 2) expression of wild type tumour suppressor genes [ 5 ]; 3) expression of genes able to solicit specific antitumour immune responses and 4) targeted silencing of oncogenes.

One approach relied on thymidine kinase (TK) gene delivery, followed by administration of prodrug ganciclovir to activate its expression and induce specific cytotoxicity [ 161 ]. This has been clinically translated for the treatment of prostate cancer and glioma [ 162 – 164 ]. In recent decades, different vectors carrying the p53 tumour suppressor gene have been evaluated for clinical applications. ONYX-015 has been tested in NSCLC patients and gave a high response rate when administered alone or together with chemotherapy [ 165 ]. Gendicine, a recombinant adenovirus carrying wild-type p53 in head and neck squamous cell cancer had a similar success, inducing complete disease regression when combined with radiotherapy [ 166 ].

Despite many achievements, there are still some challenges to face when dealing with gene therapy, such as the selection of the right conditions for optimal expression levels and the choice of the best delivery system to univocally target cancer cells. Gene therapy also presents some drawbacks linked to genome integration, limited efficacy in specific subsets of patients and high chances of being neutralised by the immune system. Therefore, particular interest has been elicited by targeted gene silencing approaches.

RNA interference (RNAi) has been recently established as an efficient technology both for basic research and medical translation. Small interfering RNAs (siRNAs) consist of double-stranded RNAs [ 167 ] able to produce targeted gene silencing. This process is intracellularly mediated by the RNA-induced silencing complex (RISC), responsible for cleaving the messenger RNA (mRNA), thus leading to interference with protein synthesis [ 168 ]. This physiological mechanism has been demonstrated in many eukaryotes, including animals. A few years after RNAi discovery, the first clinical application for wet-age related macular degeneration treatment entered phase I clinical trial [ 169 ]. Since cancer is triggered by precise molecular mechanisms, siRNAs can be rationally designed to block desired targets responsible for cell proliferation and metastatic invasion. This strategy relies on siRNA-mediated gene silencing of anti-apoptotic proteins [ 170 ], transcription factors (i.e., c-myc gene) [ 171 , 172 ] or cancer mutated genes (i.e., K-RAS ) [ 173 ]. Most of the clinical trials currently ongoing are based on local administration of siRNA oligonucleotides in a specific tissue/organ or on systemic delivery throughout the entire body [ 9 , 174 ]. Using siRNA-based drugs has several advantages: 1) safety, since they do not interact with the genome; 2) high efficacy, because only small amounts can produce a dramatic gene downregulation; 3) possibility of being designed for any specific target; 4) fewer side effects when compared to conventional therapies and 5) low costs of production [ 175 , 176 ]. However, siRNAs are relatively unstable in vivo and can be phagocytosed during blood circulation, excreted by renal filtration, or undergo enzymatic degradation [ 177 ]. Occasionally, they can induce off-target effects [ 178 ] or elicit innate immune responses, followed by specific inflammation [ 179 , 180 ]. Since naked siRNAs are negatively charged hydrophilic molecules, they cannot spontaneously cross cell membranes. Consequently, different delivery strategies are currently under study, such as chemical modification, encapsulation into lipid or polymeric carriers or conjugation with organic molecules (polymers, peptides, lipids, antibodies, small molecules [ 181 ], for efficient targeting [ 182 , 183 ]). Chemical modifications include the insertion of a phosphorothioate at 3’ end to reduce exonuclease degradation [ 184 ], the introduction of 2’ O-methyl group to obtain longer half-life in plasma [ 185 ] and the modification by 2,4-dinitrophenol to favour membrane permeability [ 186 ]. Nevertheless, the degradation of modified siRNAs often elicits cytotoxic effects; therefore, it is preferable to design ad hoc nanocarriers.

Different cationic lipid nanoparticles, such as liposomes, micelles and solid lipid nanoparticles [ 183 ], have been exploited for siRNA loading. Cationic liposomes interact with negatively charged nucleic acids, which can be easily transfected by simple electrostatic interactions [ 187 , 188 ]. They can be constituted by 1,2-dioleoyl-3-trimethylammonium propane (DOTAP) and N-{1-(2,3-dioleoyloxy) propyl]-N,N,N-trimethylammonium methyl sulphate (DOTMA) [ 189 ]. A theranostic agent consisting of an anticancer survivin siRNA entrapped in PEGylated liposomes has been developed to achieve simultaneous localisation inside tumour cells by means of entrapped MR agents and fluorophores and reduction of proliferation in vivo [ 190 ].

Neutral liposomes based on 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) have shown high efficacy in mice models of ovarian carcinoma and colorectal cancer [ 191 , 192 ]. A phase I clinical trial is currently recruiting patients for evaluating the safety of siRNA-EphA2-DOPC when administered to patients with advanced and recurrent cancer [ 193 ].

Stable nucleic acid lipid particles (SNALPs) have been evaluated in non-human primates [ 194 ]. SiRNAs have been encapsulated in a mixture of cationic lipids coated with a shell of polyethylene glycol (PEG) [ 195 ]. SNALPs entered a phase I clinical trial in patients affected by advanced solid tumours with liver involvement [ 196 ] and a phase I/II trial for treating neuroendocrine tumours and adrenocortical carcinoma patients refractory to standard therapy [ 197 ].

SiRNAs can be condensed in cationic polymers such as chitosan, cyclodextrin and polyethylenimine (PEI). Chitosan is a natural polysaccharide that, due to its cationic charge, has been exploited as carrier for nucleic acids in vitro and in vivo [ 198 ]. Specifically, a targeted siRNA has been delivered in mice xenografts of breast cancer [ 199 ]. Cyclodextrin polymers coated with PEG, conjugated with human transferrin and carrying a siRNA called CALAA-01, inhibit tumour growth by reducing the expression of M2 subunit of ribonucleotide reductase (R2), and have entered a phase I clinical trial [ 200 ]. PEI is able to form small cationic nanoparticles containing siRNAs and it has been exploited as antitumoural, upon loading with HER-2 receptor-specific siRNA [ 201 ]. A phase II clinical trial is presently starting to evaluate siG12D LODER directed to mutated KRAS oncogene and encapsulated into a biodegradable polymeric matrix for locally treating advanced pancreatic cancer patients in combination with chemotherapy [ 202 ].

SiRNAs may be conjugated to peptides, antibodies and aptamers in order to improve their stability during circulation and to enhance cellular uptake [ 203 ]. A success is represented by siRNAs targeting PSMA, overexpressed in this type of cancer [ 204 ].

The introduction of nanocarriers has largely improved siRNAs stability, pharmacokinetics and biodistribution properties, and the targeting specificity [ 205 , 206 ]. Smart nanomaterials responsive to external (i.e., magnetic field, ultrasounds) and tumour-specific stimuli (i.e., acidic pH, redox conditions) are currently under the development for controlled release and reduction of undesired negative effects [ 207 , 208 ]. Nanocarriers delivering siRNAs undergo a series of pH variations from blood circulation to intracellular environment and, for this reason, many pH responsive materials have been designed to favour cargo release under specific pH conditions [ 209 ]. Poly(allylamine) phosphate nanocarriers, stable at physiological pH, have been developed to release siRNAs in the cytoplasm after disassembly at low endosomal pH [ 210 ].

Although there have been many successes, some questions remain open and make the clinical translation of the siRNA-based approach very challenging, such as the correct doses to be delivered to patients and the many variabilities observed between individuals and different stages of disease. Further research towards controlled release to reach only specific targets, and the set-up of the best personalised therapy for cancer patients will be necessary in the near future.

Thermal ablation and magnetic hyperthermia

Thermal ablation of tumours includes a series of techniques that exploit heat (hyperthermia) or cold (hypothermia) to destroy neoplastic tissues [ 13 ]. It is known that cell necrosis occurs at temperatures lower than -40°C or higher than 60°C. Long exposures to temperatures between 41°C and 55°C are also effective for tumour cell damage. Moreover, it has been shown that cancer cells are more sensitive to high temperatures than healthy ones [ 211 ].

Hypothermic ablation is due to the formation of ice crystals upon cooling, which destroy cell membranes and finally kill cells. Argon gas is the preferred cooling agent because it can cool down the surrounding tissues to -160°C. Also, gases at their critical point, such as nitrogen, can be exploited since they have a higher heat capacity than argon. However, the technology to control and direct them is not well developed yet [ 10 ].

Hyperthermic ablation currently comprises radiofrequency (RF), microwave and laser ablation [ 10 ].

RF ablation is the most used in clinics, because it is effective and safe [ 212 ]. An alternated current of RF waves is applied to a target zone by an insulated electrode tip, while a second electrode, needed to close the circuit, is placed on the skin surface [ 10 ]. The interaction with the current causes the oscillation of ions in the extracellular fluid, which, in turns, produces heat. The more conductive the medium, the more effective the process. For this reason, RF ablation works very well in the liver and in other areas with a high content of water and ions, whereas it has a poor effect in lungs [ 10 ]. Moreover, the efficiency of the treatment decreases with the size of the lesion, giving the best results for areas not larger than 3 cm 2 [ 213 , 214 ].

Microwave ablation is based on the electromagnetic interaction between microwaves and the polar molecules in tissues, like water, that causes their oscillation and the consequent increase in temperature. Unlike the electrical current in RF ablation, microwaves can propagate through any kind of tissue [ 215 , 216 ], and this allows high temperatures to be reached in a short amount of time, to have a deeper penetration and to treat larger areas of tumours [ 217 ].

Laser therapy exploits the properties of laser beams of being very narrow and extremely focused at a specific wavelength. This makes the treatment very powerful and precise, thus a promising alternative to conventional surgery [ 218 ]. The absorption of the light emitted by the laser results in the heating and subsequent damage of the treated area [ 219 ]. Depending on the specific application, different kinds of lasers can be used. Neodymium:yttrium-aluminium-garnet (Nd:YAG) lasers (wavelength of 1064 nm) and diode lasers (wavelength of 800–900 nm) are used to treat internal organs, since they have a penetration depth up to 10 cm [ 218 ]. Conversely, CO 2 lasers (10,600 nm), with a penetration depth of 10 μm up to 1 mm maximum are used for superficial treatments. Laser therapy is receiving a lot of attention in research because of its advantages compared to other ablation techniques, such as a higher efficacy, safety and precision, and a shorter treatment session needed to achieve the same results [ 220 , 221 ]. Moreover, the fibres to transmit laser light are compatible with MRI, allowing for a precise measure of the temperature and the thermal dose [ 222 ]. However, there are still some limitations to overcome, such as the need of a very skilled operator to place the fibre in the correct position [ 218 ].

Finally, a new way to heat tumour tissues, currently under study, is through magnetic hyperthermia. This technique exploits superparamagnetic or ferromagnetic nanoparticles that can generate heat after stimulation with an alternating magnetic field. The most studied systems in nanomedicine are SPIONs [ 11 ]. The production of heat, in this case, is due to the alignment of magnetic domains in the particles when the magnetic field is applied, and the subsequent relaxation processes (Brownian and/or Neel relaxations) during which heat is released, when the magnetic field is removed and the magnetisation of the particles reverts to zero [ 223 ]. Magnetic hyperthermia can reach any area of the body and SPIONs can also act as MRI contrast agents to follow their correct localisation before the stimulation. The particles can be coated with biocompatible polymers and/or lipid and functionalized with specific ligands to impart targeting properties [ 224 ]. As already mentioned, until now, just a formulation of 15-nm iron oxide nanoparticles coated with aminosilane (Nanotherm) obtained approval for the treatment of glioblastoma [ 31 ]. SPIONs have also been successfully encapsulated in lipid nanocarriers together with a chemotherapeutic agent to combine chemotherapy and hyperthermia [ 49 , 50 ].

Recent innovations in cancer therapy: Radiomics and pathomics

Efficient cancer therapy currently relies on surgery and, in approximately 50% of patients, on radiotherapy, that can be delivered by using an external beam source or by inserting locally a radioactive source (in this case, the approach is named brachytherapy), thus obtaining focused irradiation. Currently, localisation of the beam is facilitated by image-guided radiotherapy (IGRT), where images of the patient are acquired during the treatment allowing the best amount of radiation to be set. Thanks to the introduction of intensity-modulated radiotherapy (IMRT), radiation fields of different intensities can be created, helping to reduce doses received by healthy tissues and thus limiting adverse side effects. Finally, by means of stereotactic ablative radiotherapy (SABR), it has become feasible to convey an ablative dose of radiation only to a small target volume, significantly reducing undesired toxicity [ 225 ].

Unfortunately, radioresistance can arise during treatment, lowering its efficacy. This has been linked to mitochondrial defects; thus, targeting specific functions have proven to be helpful in restoring anti-cancer effects [ 226 ]. A recent study has shown, for example, that radioresistance in an oesophageal adenocarcinoma model is linked to an abnormal structure and size of mitochondria, and the measurement of the energy metabolism in patients has allowed discrimination between treatment resistant and sensitive patients [ 227 ]. Targeting mitochondria with small molecules acting as radiosensitizers is being investigated for gastrointestinal cancer therapy [ 228 ].

Cancer is a complex disease and its successful treatment requires huge efforts in order to merge the plethora of information acquired during diagnostic and therapeutic procedures. The ability to link the data collected from medical images and molecular investigations has allowed an overview to be obtained of the whole tridimensional volume of the tumour by non-invasive imaging techniques. This matches with the main aim of precision medicine, which is to minimise therapy-related side effects, while optimising its efficacy to achieve the best individualised therapy [ 229 ].

Radiomics and pathomics are two promising and innovative fields based on accumulating quantitative image features from radiology and pathology screenings as therapeutic and prognostic indicators of disease outcome [ 12 , 13 , 230 ]. Many artificial intelligence technologies, such as machine learning application, have been introduced to manage and elaborate the massive amount of collected datasets and to accurately predict the treatment efficacy, the clinical outcome and the disease recurrence. Prediction of the treatment response can help in finding an ad hoc adaptation for the best prognosis and outcome. Nowadays, personalised medicine requires an integrated interpretation of the results obtained by multiple diagnostic approaches, and biomedical images are crucial to provide real-time monitoring of disease progression, being strictly correlated to cancer molecular characterisation.

Radiomics is intended as the high throughput quantification of tumour properties obtained from the analysis of medical images [ 14 , 15 , 231 ]. Pathomics, on the other side, relies on generation and characterisation of high-resolution tissue images [ 16 , 232 , 233 ]. Many studies are focusing on the development of new techniques for image analysis in order to extrapolate information by quantification and disease characterisation [ 234 , 235 ]. Flexible databases are required to manage big volumes of data coming from gene expression, histology, 3D tissue reconstruction (MRI) and metabolic features (positron emission tomography, PET) in order to identify disease phenotypes [ 236 , 237 ].

Currently, there is an urgent need to define univocal data acquisition guidelines. Some initiatives to establish standardised procedures and facilitate clinical translation have been already undertaken, such as quantitative imaging network [ 238 ] or the German National Cohort Consortium [ 239 ]. Precise description of the parameters required for image acquisition and for the creation and use of computational and statistical methods are necessary to set robust protocols for the generation of models in radiation therapy. According to the US National Library of Medicine, approximately 50 clinical trials involving radiomics are currently recruiting patients, and a few have already been completed [ 240 ].

Conclusions and future perspectives

In recent years, research into cancer medicine has taken remarkable steps towards more effective, precise and less invasive cancer treatments ( Figure 1 ). While nanomedicine, combined with targeted therapy, helped improving the biodistribution of new or already tested chemotherapeutic agents around the specific tissue to be treated, other strategies, such as gene therapy, siRNAs delivery, immunotherapy and antioxidant molecules, offer new possibilities to cancer patients. On the other hand, thermal ablation and magnetic hyperthermia are promising alternatives to tumour resection. Finally, radiomics and pathomics approaches help the management of big data sets from cancer patients to improve prognosis and outcome.

Figure 1. Cancer therapy approaches: The image represents the most innovative strategies to treat cancer, combining different disciplines to obtain the most efficient and personalised therapy for patients.

At the moment, the most frequent entries concerning cancer therapies in the database of clinical trials ( www.clinicaltrials.gov ) involve the terms targeted therapy, immunotherapy and gene therapy, highlighting that these are the most popular methodologies under investigation, especially because, as already mentioned before, they have been shown to be very promising and effective ( Figure 2A ). However, Figure 2B shows that the clinical trials started in the past decade on different therapies mentioned in this review (except for liposomes-based therapies) have increased in number, showing how the interest on these new approaches is quickly growing in order to replace and/or improve conventional therapies. In particular, radiomics, immunotherapy and exosomes are the entries whose number has increased the most in the last 10 years.

Figure 2. Cancer clinical trials. (A): Total number of clinical trials currently registered on www.clinicaltrials.gov for each approach discussed in this review. (B): Number of the clinical trials [in % respect with the total studies shown in (A)] started during the years 2008–2010 (blue) and from 2017 until today (orange). Date accessed: 01/08/19.

The current scenario for cancer research is wide, offering many possibilities for the constant improvement of treatment, considering not only patient recovery but also caring for their well-being during therapy. As summarised in Table 1 , these new approaches offer many advantages compared to conventional therapies. However, some disadvantages still have to be overcome to improve their performances. Much progress has been made, but many others are likely to come in the near future, producing more and more ad hoc personalised therapies.

Table 1. Advantages and disadvantages of the main innovative cancer therapeutic approaches.

Conflicts of interest.

The authors declare that they have no conflict of interest.

Funding declaration

This work was partially supported by the Fondazione CaRiPLo, grant no. 2018-0156 (Nanotechnological countermeasures against Oxidative stress in muscle cells Exposed to Microgravity—NOEMI) and by the European Research Council (ERC) under the European Union’s Horizon 2020 Research and Innovation Programme (grant agreement N°709613, SLaMM).

Authors’ contributions

Carlotta Pucci and Chiara Martinelli contributed equally to this work.

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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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• Published: 24 March 2021

Advancing Cancer Therapy

Nature Cancer volume  2 ,  pages 245–246 ( 2021 ) Cite this article

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Cancer therapies have evolved considerably in recent decades, substantially improving the quality of life and survival of patients with cancer. In this issue, we launch our Series on Cancer Therapy, exploring current paradigms and recent advances and challenges in this field, through specially commissioned articles.

The earliest evidence of cancer treatment can be traced back to an ancient Egyptian medical text, written around 3000 BC and known widely as the ‘Edwin Smith Papyrus’, that described the cauterization of breast tumors for which, according to the text, there was no cure . The situation is very different now, as, depending on breast cancer subtype, stage and demographic factors, the 5-year survival rates for this disease can surpass 90% in developed countries. For cancer types that are responsive to therapy, including certain subtypes of breast, blood and prostate malignancies, patients now face the management of a chronic disease, rather than a fatal one, owing to the rapid advances in clinical oncology over recent decades. Similarly, the prognosis for several other cancer types has also been improving. For example, patients with melanoma, which used to be considered a deadly disease, have much better prospects thanks to the breakthroughs in targeted and immune-based therapies.

These advances reflect the focus placed on cancer research and oncology by governments, funders and research institutes across the globe over the past several decades. In the USA, 2021 marks the 50-year anniversary of the signing of the National Cancer Act into law, which marked the beginning of a concerted effort to address cancer as a leading cause of death in the USA at the federal level. The National Cancer Program that arose from this initiative resulted in a profound institutional reorganization within the National Institutes of Health, with the overarching goal of developing the infrastructures required ‘for the treatment, cure, and elimination of cancer’. Other countries and international agencies also adopted cancer-focused initiatives over the years, including, for example, the PRIME scheme of the European Medicines Agency, which supports the development of medicines that target an unmet medical need, including cancer, through accelerated planning, evaluation and approval processes.

Thus, substantial progress has been made across first-line cancer therapy modalities. Surgery continues to be a first-line treatment for many cancer types, but it now includes precision and minimally invasive surgery, molecular imaging support and, more recently, robot- or artificial intelligence–assisted surgical procedures. The clinical use of one of the most widely used treatment modalities, chemotherapy, has been improved through better dosing regimens, neoadjuvant or adjuvant administration, and combination therapies. Similarly, radiation oncology has been advanced through precision radiotherapy. First-line recommendations depend on the cancer type and stage at diagnosis, and have continued to be modified as new therapeutic modalities have become available. The advent of targeted therapy and immunotherapy has revolutionized the treatment of cancer, especially with the development and availability of sophisticated diagnostic and molecular characterization technologies. Among these, ‘-omics’ techniques stand out for increasingly enabling a more precise and granular molecular characterization of cancer types and subtypes and the identification of biological correlates of response to specific therapies, thereby enriching the roster of biomarkers at the disposal of clinicians.

Targeted therapies have swiftly taken a prominent position in cancer research and clinical oncology in recent decades, thanks to the molecular insights into oncogenic processes and mechanisms gained from fundamental research and technological development. A key example of how basic research on oncogenic alterations translated into substantial clinical benefits for a large number of patients is BCR-ABL1 tyrosine-kinase inhibitors for chronic myeloid leukemia. The first BCR-ABL1 tyrosine-kinase inhibitor was discovered through drug screens in 1992, and in 2001 it became the first-line therapy with long-term remission rates for BCR-ABL–driven chronic myeloid leukemia 1 ; second-generation tyrosine-kinase inhibitors, rationally designed to circumvent acquired resistance, earned approval from the US Food and Drug Administration as frontline therapies only a decade later. More recently, the announcement of the two first-in-class inhibitors of the mutant kinase KRAS G12C was a milestone in the decades-long efforts to study and treat tumors bearing these, up-to-now considered undruggable, KRAS mutations 2 . However, not every effort in precision oncology and targeted therapy is yielding similarly positive results, especially given the issue of adaptive and acquired resistance, a complication of therapy that a large part of the cancer-research community is striving to address. It should also be noted that advances in sophisticated cancer therapeutics are sometimes associated with a high financial burden for patients, a pressing societal issue tied to the complexities of addressing the challenge of cancer 3 .

In light of the progress made so far and the goals and challenges ahead, we are pleased to launch in this issue of Nature Cancer a Series on Cancer Therapy comprising specially commissioned Review, Perspective, News and Comment articles and a collection of relevant primary research articles published in Nature Cancer . The series is housed in a dedicated page on the Nature Cancer website and will be continually updated with additional content from key opinion leaders discussing novel therapeutic opportunities, the path to drug discovery, and how these advances are transforming clinical practice.

Our series launches with two Review articles that focus on different but important aspects of cancer treatment. Whereas substantial achievements have been witnessed in the treatment of primary tumors, progress has been more modest for metastatic disease. Yibin Kang and colleagues discuss the clinical challenge of treating metastatic disease, and how preclinical and mechanistic knowledge accumulated over the years is being translated into tangible clinical benefits for disseminated disease 4 . The authors also discuss the challenges of running clinical trials for metastatic disease, and the different degrees of success of clinical trials in the metastatic setting. In a separate Review, Frank McCormick and colleagues discuss the multiple and complex links between oncogenic KRAS—one of the most frequently mutated and, as noted above, hard-to-target cancer drivers—and metabolism, highlighting the potentially targetable vulnerabilities that arise at the interface of the two 5 . Although various aspects of targeting KRAS-dependent cancer metabolism have been explored extensively in preclinical settings, ongoing and future clinical trials will hopefully shed light on the translatability of these approaches to the clinic.

Despite the many milestones achieved in cancer treatment, much remains to be addressed. In future issues we will present additional pieces focusing on a breadth of topics under this theme, including key pathways deregulated in cancer, such as EGFR or PI3K, and ongoing clinical approaches for preventing and bypassing therapy resistance. Future issues will also discuss progress in radiotherapy, immunotherapy and therapy combinations, as well as new therapeutic modalities, such as bispecific antibodies, and innovative drug-development approaches through the implementation of artificial intelligence.

Through this selection of commissioned and primary research publications, we aim to underscore how much cancer therapy has advanced over the past several decades, which goals need to be prioritized, and the challenges that should be overcome to continue improving quality of life and outcomes for patients with cancer. We thank our authors and referees for their valuable contributions and hope that our readers will find this Series on Cancer Therapy informative and inspiring.

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Cancer Treatment Research

The Importance of Cancer Treatment Research

Research on the treatment of cancer is fundamental to improving outcomes for all patients affected by the disease. Treatment advances, in combination with innovative diagnostic tools, are leading to therapies that are increasingly tailored to the cancer’s unique traits.

But despite the tremendous progress made in recent decades in treating many types of cancer, effective therapies are still lacking for some cancers, including liver cancer, pancreatic cancer, and certain types of adult and pediatric brain cancer. And even when effective therapies are available, these often stop working as the cancer develops resistance to the treatment.

Also, many people with cancer experience severe side effects of the disease and its treatment. Some of these toxic effects have long-term consequences, including an increased risk of a second cancer . For childhood cancer survivors in particular, the long-term effects of cancer treatment can have a lifelong impact on their quality of life.  

NCI-supported researchers are developing more effective and potentially less toxic treatments, such as targeted therapies, immunotherapies, and cancer vaccines, that are designed to spare healthy tissues more so than systemic treatments. In parallel, researchers continue to improve therapies that have existed for decades, such as chemotherapy, radiation therapy, and surgery. And some studies test whether less intensive therapy, with fewer side effects during and after treatment, can still effectively treat cancer.

Thanks to NCI-funded research, patients with cancer have a greater number of therapeutic options than ever before, many of which are more effective and less toxic than earlier options. But more research is needed to ensure the most effective treatment possible, including better ways to use existing therapies in combination, while maintaining the highest possible quality of life for every individual with cancer.

Selected NCI Activities in Cancer Treatment Research

For more than 50 years, NCI has played an active role in cancer drug development—from conducting preclinical studies in the laboratory to testing potential therapies in humans.

NCI researchers conduct clinical trials to test cancer treatments at the National Institutes of Health in Bethesda, MD, and the institute sponsors trials at cancer centers, hospitals, and community practices around the country. The  Cancer Therapy Evaluation Program (CTEP) functions as the institute’s primary clinical evaluator of new anticancer agents, radiation treatments, and surgical methods.

While many companies and institutions around the world conduct research on cancer treatments, NCI meets needs that industry does not. These include developing and testing treatments for rare cancers and conducting trials to test the safety and effectiveness of using less treatment or no treatment at all.

Examples of NCI-supported activities in treatment research include:

Discovering New Cancer Drugs

NCI Treatment Research and the National Cancer Plan

NCI supports a broad variety of research that aligns with the National Cancer Plan’s goal to develop effective treatments. Read about the plan and this goal.

• NCI’s  Developmental Therapeutics Program (DTP) provides free services and resources to the academic and private-sector research communities worldwide to facilitate the discovery and development of new anticancer agents, including targeted therapies that work through cancer’s unique genetic alterations. DTP supports all stages along the critical path of preclinical drug discovery and development, from high-throughput tumor cell–based screening to first-in-human clinical trials.
• The NCI-60 Human Tumor Cell Lines Screen , which includes 60 human tumor cell lines representing nine different types of cancer, is a free resource available to the research community worldwide to evaluate compounds for anticancer activity. The NCI-60 screen tests up to 7,000 compounds yearly and prioritizes compounds with promising anticancer potential for further evaluation.
• The Comparative Oncology Program is a unique program that helps researchers improve the assessment of novel therapies for humans by treating pet animals with naturally occurring cancers. The program gives these animals the benefit of cutting-edge research and therapy, and it provides researchers a better understanding of cancer biology and cancer's response to treatment.

Understanding Treatment Response

• The Acquired Resistance to Therapy Network (ARTNet) uses team science to study the mechanisms of acquired resistance to cancer therapies and disease recurrence. This program replaces and builds on progress made by the  Drug Resistance and Sensitivity Network (DRSN) , an NCI and Cancer Moonshot–created program to explore why some cancer cells are innately sensitive to treatment and to identify strategies for circumventing drug resistance in tumors.
• NCI contributes to the international  Human Cancer Models Initiative , which generates novel human tumor-derived culture models with the goal of creating cancer models that replicate patients’ tumors as faithfully as possible. The models are annotated with genomic and clinical data and are available to the wider research community to define cancer pathways, determine mechanisms of drug resistance, and assess responses to small molecules.

Improving Current Cancer Treatments

NCI FY26 Annual Plan & Professional Judgment Budget Proposal

Each year, NCI prepares a plan for advancing cancer research and proposes the budget required to fund a broad research portfolio.

• NCI’s first-of-its kind precision medicine trial called Molecular Analysis for Therapy Choice (NCI-MATCH) tested the effectiveness of treating tumors in adults and children based on matching targeted therapies to specific genetic alterations in the tumors, regardless of tumor type. Using information learned from NCI-MATCH, three more precision medicine trials—called ComboMATCH, MyeloMATCH, and iMATCH —will test whether drug combinations can overcome resistance to treatment, evaluate new treatments for myeloid leukemia and myelodysplastic syndrome, and examine immune profiles and tumor markers for responsiveness to immunotherapy, respectively.
• NCI’s  Radiation Research Program (RRP) provides expertise to investigators who perform radiotherapy studies and helps direct radiation research. Methods that more precisely target radiation therapy to tumors while sparing as much normal tissue as possible are critical for maintaining patients’ quality of life and improving cure rates.
• Immunotherapy is a type of cancer treatment that helps cells in a patient’s own immune system detect and eliminate cancer, including some difficult-to-treat tumors. Researchers are working collaboratively through the Immuno-Oncology Translational Network (IOTN) and the Pediatric Immunotherapy Network (PIN) to speed up the development of new immunotherapies to treat and prevent adult and pediatric cancers.
• NCI brings together researchers from across the institute and the National Institutes of Health to work on cancer immunology and immunotherapy research to discover, develop, and deliver immunotherapy approaches that can prevent and treat cancer and cancer-associated viral diseases. This work has pioneered important research on the basic mechanisms of immune response, including how immune system cells and cancer cells interact, and on the development of better vaccines and immunotherapies.

Moving Discoveries into the Clinic

• The  Translational Research Program (TRP) supports efforts through the Specialized Programs of Excellence (SPOREs) to translate novel scientific discoveries from the laboratory to the clinic for testing in humans. This work includes determining the biological basis for observations made in cancer patients or in populations at risk for cancer.
• The  NCI Experimental Therapeutics Program (NExT)  focuses on advancing discoveries in basic and clinical research into new therapies to treat cancer patients. This translational research effort unites the drug development expertise of multiple NCI research programs and the facilities at the NIH Clinical Center to advance new therapeutic interventions from both the private and public sectors.

Supportive Care, Symptom Management, and the National Cancer Plan

NCI supports research on supportive care and symptom management to improve the lives of people living with cancer. This research aligns with the National Cancer Plan’s goal to deliver optimal care. Read about the plan and this goal.

Supportive Care and Symptom Management

• The Supportive Care and Symptom Management program focuses on the prevention and treatment of acute and chronic symptoms and side effects related to cancer and its treatment, such as fatigue, musculoskeletal pain, nerve damage, and fertility issues. Researchers also study the effect of treatment on cancer patients' quality of life and the psychosocial issues and strategies for care at the end of life.
• NCI has established a collaborative research consortium, called  Improving the Management of Symptoms during and following Cancer Treatment (IMPACT) , to determine the best approaches for symptom management in cancer care delivery. Research centers within this consortium are testing integrated symptom monitoring and management systems in the clinic and analyzing the effects of those systems on patient outcomes, cancer treatment delivery, and health care utilization using randomized designs.

Recent Research Findings in Cancer Treatment

• Immunotherapy approach shows potential in some people with metastatic solid tumors
• Combination targeted treatment produces lasting remissions in people with resistant aggressive B-cell lymphoma
• Spurred by Survivors, Researchers Are Revisiting Cancer Drug Doses
• NIH scientists develop AI tool to predict how cancer patients will respond to immunotherapy
• NIH researchers develop AI tool with potential to more precisely match cancer drugs to patients
• First Cancer TIL Therapy Gets FDA Approval for Advanced Melanoma
• Toripalimab Becomes First Immunotherapy Drug Approved for Nasopharyngeal Cancer
• Researchers Develop a Potential “Universal” CAR T-Cell Therapy for Blood Cancers