Checkpoints: PD-1, CTLA-4, LAG-3
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.
Diagram
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.
What happens
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 molecular players
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.
Where medicines act
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.
- CemiplimabApprovedNon-small-cell lung cancerMelanomaPD-L1-high non-small-cell lung cancer without a driver mutation
- NivolumabApprovedMelanomaNon-small-cell lung cancerRenal cell carcinoma
- PembrolizumabApprovedMismatch repair deficient (MSI-high) pancreatic ductal adenocarcinomaTriple-negative breast cancer (TNBC)Non-small-cell lung cancer
- Relatlimab + nivolumabApprovedMelanomaAdvanced melanoma (unresectable stage III and stage IV)
- CadonilimabApprovedCervical cancerGastric & gastro-oesophageal junction cancer
- CamrelizumabApprovedOesophageal cancerHepatocellular carcinomaNon-small-cell lung cancer
- Camrelizumab + rivoceranibApprovedHepatocellular carcinoma
- DostarlimabApprovedMismatch repair deficient (MSI-high) pancreatic ductal adenocarcinomaEndometrial cancerColorectal cancer
- +23 more at PD-1 →
- AtezolizumabApprovedNon-small-cell lung cancerSmall-cell lung cancerHepatocellular carcinoma
- DurvalumabApprovedNon-small-cell lung cancerSmall-cell lung cancerBiliary tract cancer (cholangiocarcinoma)
- TiragolumabNegative
- AdebrelimabApprovedSmall-cell lung cancerExtensive-stage small-cell lung cancer
- AvelumabApprovedBladder & urothelial cancerRenal cell carcinomaMerkel cell carcinoma
- BenmelstobartApprovedSmall-cell lung cancerExtensive-stage small-cell lung cancer
- CosibelimabApprovedCutaneous squamous cell carcinomaAdvanced cutaneous squamous cell carcinoma
- EnvafolimabApprovedColorectal cancerCancer of unknown primary (CUP)
- +13 more at PD-L1 →
- IpilimumabApprovedMelanomaRenal cell carcinomaColorectal cancer
- TremelimumabApprovedNon-small-cell lung cancerHepatocellular carcinomaAdvanced hepatocellular carcinoma (BCLC C)
- GotistobartPhase 3
- ADG126Phase 2
- BA3071Phase 2
- BotensilimabPhase 2
- JK08Phase 2
- FianlimabPhase 3
- FavezelimabPhase 3
- HLX26Phase 2
- Axicabtagene ciloleucelApprovedDiffuse large B-cell lymphomaPrimary mediastinal (thymic) large B-cell lymphoma
- BlinatumomabApprovedAcute lymphoblastic leukaemiaStandard-risk B-cell acute lymphoblastic leukaemia in childrenRelapsed and refractory acute lymphoblastic leukaemia in children
- Brexucabtagene autoleucelApprovedMantle cell lymphomaAcute lymphoblastic leukaemia
- Inaticabtagene autoleucelApprovedAcute lymphoblastic leukaemia
- Lisocabtagene maraleucelApprovedChronic lymphocytic leukaemiaDiffuse large B-cell lymphomaRelapsed or refractory chronic lymphocytic leukaemia
- Loncastuximab tesirineApprovedDiffuse large B-cell lymphoma
- Obecabtagene autoleucelApprovedAcute lymphoblastic leukaemia
- Relmacabtagene autoleucelApprovedDiffuse large B-cell lymphomaFollicular lymphoma
- +18 more at CD19 →
How tumours escape
Records tied to this stage that describe resistance, evasion or tolerance. The resistance atlas lists the routes class by class.
- early clinicalindustryVaccines aimed only at mutations shared by every tumour cell
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.
- speculativeresearchTest protein and resistance training during immunotherapy
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.
- speculativeresearchVaccinate against the resistance mutation before it takes over
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.
- 2024rctNADINA: two doses of ipilimumab plus nivolumab before surgery beat a year of nivolumab after surgery in stage III melanomaNew England Journal of Medicinechanged practice
- 2024rctNIAGARA: durvalumab before and after cystectomy for muscle-invasive bladder cancerNew England Journal of Medicinechanged practice
- 2024rctNICHE-2: a month of nivolumab and ipilimumab before surgery clears mismatch-repair-deficient colon cancer in most patientsNew England Journal of Medicinechanged practice
- 2024translationalNICHE-2: a single dose of ipilimumab and two of nivolumab before surgery clears dMMR colon cancer in most patientsNew England Journal of Medicinechanged practice
- 2023translationalRojas 2023: a personalised mRNA vaccine trained T cells against each patient's pancreatic cancer, and those who responded stayed cancer-free longerNature
- 2022rctCheckMate 816: three cycles of nivolumab plus chemotherapy before lung cancer surgeryNew England Journal of Medicinechanged practice
Measured by
Biomarkers, tests and assays in the corpus that read this stage in a patient.
- PD-L1 IHC 22C3 pharmDxIHC
- PD-L1 IHC 28-8 pharmDxIHC
- FoundationOne CDxNGS tissue
- VENTANA MMR RxDx PanelIHC
- MSI by PCR (Promega MSI Analysis System and equivalents)PCR
- Tumour mutational burden (FoundationOne CDx and equivalents)NGS tissue
- VENTANA PD-L1 (SP142) AssayIHC
- VENTANA PD-L1 (SP263) AssayIHC
- Signatera (tumour-informed ctDNA MRD)NGS plasma
Open questions
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.
- Which second checkpoint adds real benefit, and for whom (LAG-3 yes in melanoma; TIGIT mixed)?
- Can exhaustion be reversed at the epigenetic level?
- being tested at scaleresearchRandomised trials of stopping immunotherapy after one year versus continuing
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.
- being tested at scaleclinicStanding reflex biomarker panels per tumour type, run without an oncologist's order
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.
- being tested at scaleTIL-based omission of chemotherapy in stage I TNBC
Small triple-negative tumours packed with immune cells almost never come back. The idea is to skip chemotherapy for those patients.
- being tested at scaleresearchUse pre-surgery immunotherapy windows as the field's biomarker engine
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.
- early clinicalindustryA single calibrated tumour mutational burden across all sequencing panels
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.
- early clinicalBiomarker-directed first-line quadruplets in gastric cancer
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.
- early clinicalBRAF/MEK plus PD-1 blockade as standard for BRAF-mutant anaplastic thyroid cancer
Add immunotherapy to the two targeted pills in the most aggressive thyroid cancer, because the combination has produced multi-year survivors in early series.
- early clinicalCD8 PET to stop or switch immunotherapy early
Scan for T cells inside the tumour a few weeks after starting immunotherapy. If they have not arrived, change course.
- early clinicalindustryClear the suppressive neutrophils out of pancreatic tumours first
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.
- early clinicalresearchConfirm ultra-low-dose immunotherapy so it can be afforded where most patients live
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.
48 more ideas are linked to this stage's pathways, targets and terms; see the rankings →
Key evidence
Papers in the corpus tied to this stage's pathways, targets and terms, newest first.
- 2025rctCheckMate 067 at ten years: half of melanoma patients treated with nivolumab plus ipilimumab were alive a decade laterNew England Journal of Medicinechanged practice
- 2025rctCheckMate 067 at ten years: nivolumab plus ipilimumab produces long-term survival in half of patients with advanced melanomaNew England Journal of Medicinechanged practice
- 2025rctHARMONi-2: ivonescimab, a PD-1 x VEGF bispecific, beats pembrolizumab head-to-head in PD-L1-positive lung cancerThe Lancet
- 2025rctIMvigor011: using a blood test for leftover cancer to decide who gets immunotherapy after bladder surgeryNew England Journal of Medicinechanged practice
- 2024rctADRIATIC: durvalumab after chemoradiotherapy for limited-stage small-cell lung cancerNew England Journal of Medicinechanged practice
- 2024rctEV-302: enfortumab vedotin plus pembrolizumab replaces chemotherapy as first treatment for advanced bladder cancerNew England Journal of Medicinechanged practice
- 2024rctKEYNOTE-942: a personalised mRNA cancer vaccine plus pembrolizumab after melanoma surgeryThe Lancet
- 2024rctKEYNOTE-A18: pembrolizumab with chemoradiotherapy for locally advanced cervical cancer (overall survival)The Lancetchanged practice
- 2024rctKEYNOTE-A18: pembrolizumab with chemoradiotherapy for locally advanced cervical cancer (progression-free survival)The Lancetchanged practice
- 2024rctNADINA: two doses of ipilimumab plus nivolumab before surgery beat a year of nivolumab after surgery in stage III melanomaNew England Journal of Medicinechanged practice
- 2024rctNIAGARA: durvalumab before and after cystectomy for muscle-invasive bladder cancerNew England Journal of Medicinechanged practice
- 2024rctNICHE-2: a month of nivolumab and ipilimumab before surgery clears mismatch-repair-deficient colon cancer in most patientsNew England Journal of Medicinechanged practice
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.