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T cells carry brakes so they do not attack the body. Tumours lean on them: PD-L1 on their surface, Tregs with CTLA-4, LAG-3 and TIGIT on exhausted T cells. Checkpoint inhibitors release the brakes; exhausted cells that are only tired recover, the broken do not.
Pick a product above a diagram to see the nodes it hits and the escape routes below the block. Hover or tap any node or arrow for what it is; every node opens its target, glossary entry or the pathway page. Violet boxes are druggable targets.
A soldier needs a target in the sights (TCR) and an order to fire (CD28). CTLA-4 is a commander revoking orders during training; PD-1 is a white flag the enemy waves on the battlefield that makes the soldier lower their weapon. Checkpoint inhibitors tear up the white flag.
A soldier posted at a wall for months with no relief. First tired, then unwilling to fire, finally unable to, and the last stage is written into their habits so deeply that no order can undo it. Checkpoint inhibitors work on the tired, not the broken.
In plain words, then the glossary entries the stage rests on. Chapter 6, Escaping the immune system: Every tumour that exists has already beaten the immune system once.
T cells carry brakes so they do not attack the body. Tumours lean on them: PD-L1 on their surface, Tregs with CTLA-4, LAG-3 and TIGIT on exhausted T cells. Checkpoint inhibitors release the brakes; exhausted cells that are only tired recover, the broken do not.
PD-1 / PD-L1 immune checkpoint & T-cell activation. How T cells decide to attack. A T cell needs to see the target (TCR-MHC) and get a 'go' signal (CD28). PD-1 and CTLA-4 are 'stop' signals; tumours exploit them. Checkpoint inhibitors remove the stop.
T-cell exhaustion. T cells that see their target for weeks on end without winning gradually shut down: they raise a set of brakes (PD-1, LAG-3, TIM-3, TIGIT), lose their ability to kill, and eventually lock this state into their DNA. Checkpoint drugs rescue the ones that are only partly exhausted; the terminally exhausted are beyond reach.
The proteins and genes at this stage, with their role and how many products act on each. Listed players come from the atlas; drawn players sit as nodes in the diagrams above.
PD-1 is a brake on T cells. Blocking it releases the immune system against the tumour and has cured some previously incurable cancers.
PD-L1 is the tumour's side of the PD-1 brake, and also the biomarker that decides who gets immunotherapy.
The first immune brake ever targeted for cancer; releasing it won a Nobel Prize and cures a fraction of melanomas.
LAG-3 is the third immune brake to reach approval, combined with PD-1 blockade in melanoma.
TIGIT is an inhibitory receptor on T and natural killer cells that binds PVR (CD155) on tumour cells, so blocking it was expected to amplify PD-1 and PD-L1 inhibitors. Tiragolumab, domvanalimab and others then failed to add benefit in phase 3 lung cancer trials despite encouraging phase 2 signals, and the lack of a TIGIT-specific biomarker remains a weakness.
An immune checkpoint on exhausted T cells and on leukaemic stem cells; antibodies against it failed in lung cancer and MDS after strong preclinical promise.
CD19 is a marker on B cells and B-cell cancers, and was the target of the first CAR-T therapies ever approved.
Products grouped by the node they hit, most advanced first, with the cancers an approved product is linked to. Pick one above the diagram to see it light up.
Records tied to this stage that describe resistance, evasion or tolerance. Resistance: how tumours escape each drug class lists the routes class by class.
Two thirds of women treated on the KEYNOTE-522 regimen have no tumour left at surgery and about 92 percent of them are alive without relapse at five years, yet all receive nine more cycles of pembrolizumab. Trials are now testing whether the best responders can stop early, skip the anthracycline, or in lymphocyte-rich stage I tumours skip chemotherapy altogether.
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.
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.
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.
Biomarkers, tests and assays in the corpus that read this stage in a patient.
What is not known at this stage: the atlas's own questions, the bottlenecks it bears on, and the ideas in the corpus that try to answer them.
Immunotherapy is often given for two years or until it stops working, but responses can last long after stopping. Trials that randomly assign responders to stop or continue would show whether the extra year is needed.
For each cancer type, agree the set of stains and tests that are always needed, and have the lab run them automatically on diagnosis rather than waiting for someone to ask.
Small triple-negative tumours packed with immune cells almost never come back. The idea is to skip chemotherapy for those patients.
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.
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.
Stomach cancer now has three add-on biomarkers (HER2, PD-L1, Claudin 18.2) that often overlap. Test whether combining two add-ons beats picking one.
Add immunotherapy to the two targeted pills in the most aggressive thyroid cancer, because the combination has produced multi-year survivors in early series.
Scan for T cells inside the tumour a few weeks after starting immunotherapy. If they have not arrived, change course.
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.
A single-centre trial at Tata Memorial found that adding nivolumab at about a twentieth of the usual dose to chemotherapy improved outcomes in head and neck cancer. Confirmatory trials against standard-dose immunotherapy are needed before low-dose labels could make immunotherapy affordable for millions.
50 more ideas are linked to this stage's pathways, targets and terms; see the rankings →
Papers in the corpus tied to this stage's pathways, targets and terms, newest first.
src/data/mechanics-atlas.ts). Players, medicines, escape routes, tests, ideas and papers are resolved from the knowledge graph at build time through the stage's pathways, targets and terms, so every item here has its own page and sources. Where a section is missing, the corpus has no record tied to the stage yet. Nothing here is medical advice; see about and methodology. Stage 6.2 of 56.