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Checkpoint drugs cure some patients and do nothing for most. We still cannot tell the two apart before treating.
PD-L1 immunohistochemistry, tumour mutational burden and mismatch-repair deficiency are the approved selection biomarkers for checkpoint inhibitors, and all are imperfect: PD-L1-negative patients respond, PD-L1-high patients progress, TMB thresholds vary by tumour type and assay, and only dMMR/MSI-high is a strong discriminator. As a result checkpoint inhibitors are given to nearly half of US patients with cancer while an estimated one in eight benefits, at a cost of tens of billions of dollars and a burden of immune-related adverse events in non-responders. Better predictors will need to integrate the tumour (antigenicity, interferon signalling, antigen presentation), the microenvironment (T-cell infiltration, myeloid state), the host (HLA genotype, microbiome) and early on-treatment dynamics (ctDNA clearance, CD8 PET, radiomics). The regulatory and reimbursement systems also need to accept biomarkers that deselect patients, which no sponsor is motivated to develop.
Tumour mutational burden decides who gets immunotherapy in some settings, but every sequencing panel calculates it differently. A shared calibration would make the number mean the same thing everywhere.
Cells chop up their internal proteins and display the pieces on their surface. That means even undruggable proteins inside the cell can be attacked from outside by the immune system.
Gut bacteria appear to influence whether immunotherapy works, and diet and antibiotics shape gut bacteria. Yet almost no drug trial records what patients ate or which antibiotics they took. Recording it would cost almost nothing.
Some tumours have broken the machinery that displays their identity to immune cells. Those patients cannot benefit from most immunotherapy and should be routed elsewhere.
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.
Tumours that contain small immune structures resembling lymph nodes respond far better to immunotherapy. Inducing those structures on purpose could make cold tumours responsive.
Lab-grown mini-tumours usually contain only cancer cells. Adding the patient's own immune cells lets researchers test immunotherapy outside the body.
Most cancer drugs are tested in mice with no immune system, then given to people who have one. Mice carrying the same patient's immune cells and tumour would be a fairer test.
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.
New imaging shows where every cell type sits in a tumour slice. Using it to see which sub-populations are hidden from immune cells could explain why immunotherapy fails in parts of a tumour.
There are several different PD-L1 tests, each tied to a different drug, and they disagree. A single digitally calibrated scale would let any lab's result be translated into any drug's cut-off.
Vaccines tailored to each patient's tumour mutations are showing real benefit but cost a fortune to make. Automate the whole process so a personalised vaccine costs about as much as a course of chemotherapy.
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.
Dozens of trials have collected immune, genomic and imaging data on the same drugs. Nobody can analyse them together, so the answer stays hidden in fragments.
Immunotherapy can trigger dangerous attacks on the gut, lungs or heart. Use blood, gut bacteria and genetic markers to spot who is at risk and act early.
Antibiotics given in the weeks before immunotherapy are linked to much worse results. A simple stewardship rule could preserve benefit at no cost.
Patients who happened to take common allergy pills during immunotherapy seemed to live longer in a large records study. A simple randomised trial would show whether the pills really help.
Patients are denied a drug when a test says they will not benefit, but that restriction is usually inferred from enrichment trials rather than tested. For high-stakes markers with weak evidence in the negative group, such as PD-L1 and HER2 0, randomised trials in biomarker-negative patients should test the assumption itself.
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.
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.
Growing a patient's own tumour-fighting cells only works if those cells are there to start with. A test for them would spare futile treatment.
New microscopes can measure dozens of proteins at once and map where immune cells sit in a tumour. These readouts could predict immunotherapy response, but every lab does it differently.
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.
Targeted drugs briefly make cancer cells easier for the immune system to spot. Giving immunotherapy exactly in that window, rather than at the same time, may work better.
Immune side-effects are usually treated with high-dose steroids, which may also switch off the anti-cancer response. Targeted alternatives may control the side-effect and keep the benefit.
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.
Whether immune cells are next to cancer cells matters more than how many there are. Turning that spatial picture into a reliable, standardised test would predict response better.
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.
Scans at three months often cannot tell whether immunotherapy is working. A blood test at six weeks may give a clearer, earlier answer.
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.
Giving immunotherapy for a few weeks before surgery produces a tumour sample that shows exactly what the drug did. That is the fastest way to learn who responds.
Resistance often arrives as the same few mutations. Teaching the immune system to recognise them in advance could remove the escaping cells while they are still rare.
Personal cancer vaccines target a list of mutations, some present in only part of the tumour, so the tumour can escape by losing them. Restricting vaccines and T-cell products to clonal mutations shared by every tumour cell, identified by multi-region sequencing, should close that escape route.
When immunotherapy works, specific immune cell families multiply in the blood within weeks. Tracking that could tell patients early whether to continue.
For patients with advanced melanoma, immunotherapy offers a realistic chance of long-term survival and probably cure, and the ten-year data show that patients who are alive and progression-free at three years rarely die of melanoma afterwards. Nivolumab plus ipilimumab gives the best long-term results but at a high price in serious side effects; nivolumab alone or nivolumab plus relatlimab are alternatives for patients at lower risk or with autoimmune concerns. The trial is also a caution about surrogate endpoints: the survival plateau took years to become visible.
For the first time a new drug has beaten pembrolizumab, the global first-line standard, in a randomised lung cancer trial, and it did so by combining checkpoint blockade with anti-angiogenesis in one molecule. For patients outside China nothing changes yet: the drug is not approved in the West, the trial was single-country, and survival benefit has not been shown. If confirmed in the global HARMONi-3 and HARMONi-7 trials, PD-1 x VEGF bispecifics could replace PD-1 antibodies as the immunotherapy backbone.
Evidence that the immune environment of gallbladder cancer differs by population even when the mutations do not; a reason to report gallbladder cancer and its regions separately in immunotherapy trials rather than as one biliary subgroup.
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.
Patients with limited-stage small-cell lung cancer who complete chemoradiotherapy without progression should now be offered up to two years of durvalumab consolidation, which extends life by almost two years on average. This is the first survival improvement for limited-stage disease since twice-daily radiotherapy and prophylactic cranial irradiation, and small-cell lung cancer is no longer a disease where immunotherapy gives only marginal gains.
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.
For the first time a randomised trial suggests that a vaccine tailored to an individual's tumour can reduce relapse when combined with immunotherapy, which is a proof of concept for a field that had failed for decades. Nothing changes for patients yet: the trial was small, the confidence interval crossed one, and the phase 3 trial in melanoma (and parallel trials in lung and other cancers) must confirm it. If it does, personalised mRNA vaccines could become a routine adjunct to checkpoint inhibitors after surgery.
The survival gain turns the earlier progression-free survival result into a clear reason to offer pembrolizumab with and after chemoradiotherapy to women with node-positive or stage III-IVA cervical cancer. Because cervical cancer is concentrated in low- and middle-income countries, the benefit reaches most women only if pricing and access follow.
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 Standards for spatial and multiplex tissue biomarkers before they reach the clinic, Randomised trials to test whether biomarker-negative patients really do not benefit, A single calibrated tumour mutational burden across all sequencing panels, Use a hypoxia scan to pick patients for adenosine-pathway drugs.
Shares Perioperative nivolumab and chemotherapy in stage III non-small-cell lung cancer, Five-year survival outcomes from the PACIFIC trial: durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer, Adjuvant atezolizumab after adjuvant chemotherapy in resected stage IB-IIIA non-small-cell lung cancer (IMpower010), Perioperative durvalumab for resectable non-small-cell lung cancer.
Shares Time immunotherapy to the moment targeted drugs make tumours visible, PD-L1 Immunohistochemistry Assays for Lung Cancer: Results from Phase 1 of the Blueprint PD-L1 IHC Assay Comparison Project, Leach, Krummel and Allison: releasing the CTLA-4 brake makes mice reject tumours, Iwai and Honjo: tumours use PD-L1 to escape T cells, and blocking it restores attack.
Shares Vaccinate against the resistance mutation before it takes over, Vaccines aimed only at mutations shared by every tumour cell, Personalised cancer vaccines at commodity cost through fully automated manufacturing, Antibodies that see mutant KRAS and p53 fragments displayed on the cell surface.
Shares Sharon Belvin, Tasuku Honjo, Leach, Krummel and Allison: releasing the CTLA-4 brake makes mice reject tumours, Sean Parker.
Shares MIMic-01: healthy-donor FMT plus anti-PD-1, first-line melanoma, Centre hospitalier de l'Université de Montréal (CHUM), FMT plus pembrolizumab in anti-PD-1-refractory melanoma (Pittsburgh), Gut microbiome diversity and composition.
Shares Unmask hidden antigens with a short epigenetic course before immunotherapy, Botensilimab plus balstilimab in relapsed/refractory microsatellite stable metastatic colorectal cancer: a phase 1 trial, KEYNOTE-177, Select microsatellite stable patients for immunotherapy by a measured immune biomarker, not by how many treatments they have already failed.