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Most tumours keep the immune system out or asleep, so immunotherapy helps only a minority.
Checkpoint blockade is the one therapeutic advance of the last two decades for which more than two fifths of US cancer patients are eligible, yet it works durably in a minority of patients and barely at all in several of the cancers that kill the most people. Pancreatic, prostate, most breast and microsatellite-stable colorectal cancers and glioblastoma are 'cold': few infiltrating T cells, low neoantigen load, dense desmoplastic stroma, abundant myeloid suppressor cells and regulatory T cells, hypoxia, and metabolic competition that starves effector cells. Even in 'hot' tumours, exhaustion and antigen loss limit durability. The field has many candidate mechanisms and many single-agent attempts (IDO, TIGIT, STING agonists, oncolytic viruses, CD47) that have failed in phase 3 because the biology of each tumour's exclusion is different and largely unmeasured. Converting cold tumours, or bypassing the microenvironment with engineered cells, bispecifics and radioligands, is the central strategic problem in immuno-oncology.
TGF-beta is a signal that keeps immune cells out of tumours, but blocking it throughout the body caused bleeding and heart toxicity and sank bintrafusp alfa. Tethering the blocker to tumour stroma with a FAP anchor, a collagen-binding domain or a protease-activated mask could give the benefit without the harm.
Drugs that grab T cells and drag them onto tumours work well in blood cancers. The same trick aimed at tumour-eating cells might work where T cells are absent.
An old part of the immune system called complement can be hijacked by tumours to summon protective cells. Drugs that block it already exist for other diseases.
Cancer cells can survive a drug because surrounding normal cells feed them growth signals. Blocking those signals could make existing drugs work better and longer.
Pancreatic tumours are packed with a type of white blood cell that shuts down the immune attack. Blocking the signal that recruits them may open the tumour to immunotherapy.
Tumours are acidic, and immune cells stop working in acid. Neutralising that acid, or blocking the pumps that create it, might let immunotherapy work.
Some cancer proteins sit on the cell surface or float outside cells, where protein-destroying drugs cannot reach. A different trick can drag them inside to be broken down.
Some harmless bacteria naturally grow in the low-oxygen core of tumours. Engineering them to produce immune-activating drugs turns them into tiny factories inside the tumour.
For people at very high cancer risk, install a small population of engineered immune cells that live for years and destroy cells showing early cancer signals before a tumour forms.
Tumours that contain small immune structures resembling lymph nodes respond far better to immunotherapy. Inducing those structures on purpose could make cold tumours responsive.
A rice-grain-sized implant releases microdoses of up to 20 drugs into separate spots of a tumour for one to three days, then is removed so pathologists can see which drug worked in that person's own tumour. First-in-human studies have been done in breast, sarcoma and brain tumours.
Breathing in an immune-activating drug could turn the lungs into bad soil for cancer seeds, at doses far too low to cause body-wide side-effects.
A cheap blood pressure drug may soften the dense scar tissue around pancreatic tumours so chemotherapy and immune cells can get in. Early trials look encouraging.
Immunotherapy works in tumours that immune cells can enter and ignores those that shut them out. Systematically test ways to open up the shut-out tumours, measured with spatial maps.
The support cells that build a tumour's scaffolding come in several types: some protect the tumour, others restrain it. Treating all of them the same way explains past failures.
Focused ultrasound can break a tumour apart without heat or cuts, leaving debris the immune system can learn from. Doing that to one tumour may help treat the rest.
Interleukin-12 is an immune-stimulating cytokine that caused severe toxicity when injected into the bloodstream in the 1990s and was abandoned. An oncolytic herpes or adenovirus carrying the interleukin-12 gene under a drug-inducible promoter makes it only inside the tumour, keeping exposure local; trials include recurrent glioblastoma.
Radiation can alert the immune system through the cGAS-STING pathway, but single doses above roughly 12 to 18 Gy switch on the enzyme TREX1, which destroys the alarm signal. Choosing fractionated schedules around 8 Gy times three for immune priming may add benefit at no extra cost.
Tumours fill with immune cells that protect them. Earlier drugs tried to remove those cells and failed. Newer ones aim to switch them to the attacking side.
The liver is where bowel cancer most often spreads. Drugs delivered straight into the liver's blood supply could retrain its resident immune cells to reject arriving cancer cells.
Pancreatic tumours are mostly scar tissue. The first attempt to dissolve it, an enzyme given with chemotherapy to nearly 500 patients, shrank more tumours but did not lengthen life, and mouse work showed that stripping out the scar-forming cells made cancers worse. The proposal is to test drugs that change what the stroma does rather than remove it, in trials measured on survival.
Ninety-five percent of advanced bowel cancers ignore immunotherapy, and the only real signal so far came in patients without active liver secondaries. Trials keep enrolling by treatment line rather than by immune biology, which guarantees the responders are diluted away.
Transferring gut bacteria from patients who responded to immunotherapy has helped some patients who had stopped responding. It is time for a proper large trial.
People who eat more fibre appear to respond better to immunotherapy, while some probiotic supplements may do the opposite. A proper trial would settle it.
Muscle is an immune organ as well as a movement organ. Building it during immunotherapy might improve how well the treatment works, not just how patients feel.
Certain vaccines and fungal sugars reprogramme the bone marrow so it produces more aggressive immune cells for months. That could be used before immunotherapy.
Intracavitary immunotherapy targets cancer that coats the lining of the abdomen or chest, which drugs given by drip barely reach. Delivering it straight into the cavity gives far higher local doses.
The first lymph node cancer reaches is also where the immune system learns to fight it. Injecting immunotherapy into that node before surgery, instead of removing it blindly, may work better.
Injecting immune-activating agents into a single tumour, plus a small dose of radiation, can teach the immune system to attack tumours elsewhere in the body.
Low doses of drugs that change how DNA is packaged can make cancer cells display more of what marks them as abnormal, potentially waking up immunotherapy in cold tumours.
Tumours starved of oxygen produce a chemical that switches immune cells off. A scan can show which tumours are starved, and those are the ones to treat with blockers.
Low doses of anti-blood-vessel drugs briefly make tumour vessels work better, which helps immune cells and other drugs get in. Scans can find that window for each patient.
The strongest human evidence that a cancer vaccine can make durable T cells in a tumour with few mutations; the randomised phase 2 IMCODE003 (260 patients, primary completion listed for January 2031) is the test of whether that translates into fewer relapses.
The first credible response signal in microsatellite stable colorectal cancer, and the reason the field's attention has moved to Fc engineering and to excluding patients with active liver metastases, in whom responses are rare.
It reframes air quality as cancer policy rather than respiratory policy, and it explains the shape of lung cancer in never-smokers: the mutations are common and mostly silent, and what differs is whether something inflames the tissue enough to let one of them grow.
For fit patients with newly diagnosed metastatic pancreatic cancer, a FOLFIRINOX-type regimen is now proven to be better than gemcitabine plus nab-paclitaxel, settling a long-standing debate. The absolute gain is about two months of median survival, and the regimen is more toxic for the gut. Whether liposomal irinotecan adds anything over conventional irinotecan (standard FOLFIRINOX) has never been tested head-to-head.
Pancreatic cancer was thought to be immunologically inert because of its low mutation burden; this study showed that with the right vaccine platform its few neoantigens can still be targeted. It is the strongest human evidence so far that personalised cancer vaccines can generate durable, tumour-specific immunity, and it justifies the randomised trials now running in pancreatic cancer and melanoma. Benefit is not yet proven, because responders may simply have had more immunogenic tumours.
The measured size of the immunotherapy problem in prostate cancer: a response rate in the low single figures, no signal from PD-L1 expression, and durable benefit in a small subgroup nobody can yet identify prospectively. Any claim that immunotherapy is coming to prostate cancer has to explain this trial.
The definitive negative result for first-generation stromal targeting: a biomarker-selected population, a drug that did what it was designed to do to the matrix, and no survival benefit; the stroma ideas on this page start from here.
Two bottleneck pages and 32 idea pages on OnCo cite this paper by its DOI; this record gives the citation a page of its own so a reader can follow it without leaving OnCo. Read the abstract above alongside the citing pages listed under Related; the record was created automatically from the Europe PMC entry and its figures have not been checked by hand.
Shares Clear the suppressive neutrophils out of pancreatic tumours first, De-acidify the tumour so T cells can work in it, Test protein and resistance training during immunotherapy, Reprogramme suppressive macrophages instead of trying to delete them.
Shares Elements of cancer immunity and the cancer-immune set point, Immunogenic cell death, STING & innate immune agonists, Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial.
Shares Randomized Phase III Trial of Pegvorhyaluronidase Alfa With Nab-Paclitaxel Plus Gemcitabine for Patients With Hyaluronan-High Metastatic Pancreatic Adenocarcinoma, Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival, Nutrient competition & metabolic immunosuppression, cGAS-STING innate sensing.
Shares Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial, Making microsatellite-stable colorectal cancer immunotherapy-responsive, CheckMate 8HW, KEYNOTE-177.
Shares TIGIT, Tiragolumab, LAG-3, Tumour-infiltrating lymphocytes (TILs).
Shares INTerpath-001 (V940-001), Rojas 2023: a personalised mRNA vaccine trained T cells against each patient's pancreatic cancer, and those who responded stayed cancer-free longer, Autogene cevumeran, Intismeran autogene.
Shares Cold tumours: immune deserts and exclusion, Tumour-infiltrating lymphocytes (TILs), Neoantigen, Hot vs cold tumours.
Shares LAG-3, Hot vs cold tumours, CTLA-4, Personalised neoantigen (mRNA) vaccines.