PD-1 is a brake on T cells. Blocking it releases the immune system against the tumour and has cured some previously incurable cancers. This dossier gathers the 14 products (12 approved), 79 trials, 12 pathways and 5 resistance routes in the corpus that involve it, with external identifiers so it can be joined to UniProt, ChEMBL, Open Targets and the rest of biology.
14
products
79
trials
2
cancers with prevalence
12
pathways
5
resistance routes
0
hotspots
3
open questions
28
key papers
Biology
Inhibitory receptor on activated T cells; ligands PD-L1/PD-L2. Tumour PD-L1 expression, TMB, and MSI predict response imperfectly.
Where it is found
- Exhausted T cells in the tumour microenvironment
Cancers
Adrenocortical carcinomaAnal cancer (squamous cell carcinoma)Basal cell carcinomaBiliary tract cancer (cholangiocarcinoma)Bladder & urothelial cancerCancer of unknown primary (CUP)Cervical cancerColorectal cancerCutaneous squamous cell carcinomaEndometrial cancerGastric & gastro-oesophageal junction cancerGestational trophoblastic neoplasiaGlioma & glioblastomaHead and neck squamous cell carcinomaHepatocellular carcinomaHodgkin lymphomaKaposi sarcomaMelanomaMerkel cell carcinomaMesotheliomaNasopharyngeal carcinomaNon-small-cell lung cancerOesophageal cancerOvarian cancerPeripheral T-cell lymphomas (including cutaneous T-cell lymphoma)Primary CNS lymphomaRenal cell carcinomaSmall-cell lung cancerThymoma and thymic carcinomaThyroid cancerTriple-negative breast cancer (TNBC)Uveal melanomaVulvar cancer
Technologies aimed at it
Elsewhere: identifiers and databases
Built from HGNC, Ensembl, UniProt and ChEMBL idsPDCD1programmed cell death 1 · 2q37.3HGNCEnsemblUniProtAlphaFold DBChEMBLOpen TargetsCIViCOncoKBCOSMICcBioPortalDepMapHuman Protein AtlasNCBI GeneOMIM
How common it is, by cancer
Full matrix →| Cancer | Prevalence | Measure | Note | Source |
|---|---|---|---|---|
| Melanoma | 30-40% | Objective response to PD-1 monotherapy (proxy) | Not an expression prevalence | Wikipedia |
| Non-small-cell lung cancer | 20-45% | Response by PD-L1 stratum (proxy) | Wikipedia |
Approximate, population-level figures; the measure column says what was counted. Ranges show the midpoint as a bar.
Products by modality and phase
Browse products →| Modality | Approved | Phase 3 |
|---|---|---|
| Antibody 11 | ||
| Bispecific antibody 3 |
Trials
Evidence ranking →| Trial | Phase | Status | Setting | Result | Products |
|---|---|---|---|---|---|
| Fianlimab + cemiplimab phase 3 (first-line melanoma) NCT05352672 | 3 | Negative | Untreated unresectable or metastatic melanoma: fianlimab + cemiplimab (two dose levels) vs pembrolizumab | Primary PFS endpoint not met; numerical +5.1 months median PFS at the high dose. | |
| HARMONi-3 NCT05899608 | 3 | Mixed | First-line metastatic squamous and non-squamous NSCLC, global: ivonescimab + chemotherapy vs pembrolizumab + chemotherapy | Interim PFS not statistically significant (May 2026); final readouts pending. | |
| HERIZON-GEA-01 NCT05152147 | 3 | Positive | First-line HER2-positive advanced gastro-oesophageal adenocarcinoma: zanidatamab + chemotherapy ± tislelizumab vs trastuzumab + chemotherapy | PFS 12.4 vs 8.1 months (HR 0.63-0.65); OS significantly improved. | |
| INTerpath-001 (V940-001) NCT05933577 | 3 | Positive | Adjuvant resected stage IIB-IV melanoma: intismeran autogene + pembrolizumab vs pembrolizumab | RFS and DMFS significantly improved (HRs pending presentation). | |
| LITESPARK-012 NCT04736706 | 3 | Negative | Untreated advanced clear-cell RCC: pembrolizumab + lenvatinib ± belzutifan (or ± quavonlimab) | Primary endpoint not met (ASCO GU 2026). | |
| LITESPARK-022 NCT05239728 | 3 | Positive | Clear-cell RCC at high risk after nephrectomy: adjuvant pembrolizumab + belzutifan vs pembrolizumab + placebo | DFS significantly improved vs pembrolizumab (interim; HR presented ASCO GU 2026). | |
| ASCENT-04 / KEYNOTE-D19 NCT05382286 | 3 | Positive | First-line PD-L1+ (CPS ≥10) metastatic TNBC: sacituzumab govitecan + pembrolizumab vs chemotherapy + pembrolizumab | PFS HR 0.65; PFS2 improved. | |
| EV-303 / KEYNOTE-905 NCT03924895 | 3 | Positive | Cisplatin-ineligible MIBC: perioperative enfortumab vedotin + pembrolizumab with cystectomy vs cystectomy alone | EFS HR 0.40; OS HR 0.50; pCR 57.1% vs 8.6%. | |
| EV-304 / KEYNOTE-B15 NCT04700124 | 3 | Positive | Cisplatin-eligible MIBC: perioperative enfortumab vedotin + pembrolizumab vs neoadjuvant gemcitabine-cisplatin, both with cystectomy | EFS, OS, and pCR significantly improved (topline; details pending). | |
| KEYNOTE-689 NCT03765918 | 3 | Positive | Resectable stage III-IVA HNSCC: neoadjuvant pembrolizumab, surgery, then adjuvant pembrolizumab with (chemo)radiation vs surgery and (chemo)radiation | Median EFS 59.7 vs 29.6 months (CPS ≥1). | |
| KEYNOTE-B96 / ENGOT-ov65 NCT05116189 | 3 | Positive | Platinum-resistant recurrent ovarian cancer, 1-2 prior lines: pembrolizumab + weekly paclitaxel ± bevacizumab vs placebo + paclitaxel ± bevacizumab | OS 18.2 vs 14.0 months in CPS ≥1 (HR 0.76); ITT OS HR 0.82. | |
| RELATIVITY-098 NCT05002569 | 3 | Negative | Resected stage III/IV melanoma: adjuvant nivolumab + relatlimab vs nivolumab | RFS not improved. | |
| CheckMate 8HW NCT04008030 | 3 | Positive | MSI-H/dMMR metastatic colorectal cancer, all lines: nivolumab + ipilimumab vs nivolumab vs chemotherapy | First-line PFS 54.1 vs 5.9 months (HR 0.21); combination vs nivolumab PFS HR 0.62. | |
| CheckMate 9DW NCT04039607 | 3 | Positive | First-line unresectable HCC: nivolumab + ipilimumab vs lenvatinib or sorafenib | OS 23.7 vs 20.6 months, HR 0.79; ORR 36% vs 13%. | |
| COMPASSION-16 / AK104-303 NCT04982237 | 3 | Positive | Persistent, recurrent, or metastatic cervical cancer, first line (China): cadonilimab (PD-1×CTLA-4 bispecific) + platinum-paclitaxel ± bevacizumab vs placebo + chemotherapy ± bevacizumab | OS HR 0.64; PFS HR 0.62. | |
| HARMONi-2 NCT05499390 | 3 | Positive | First-line PD-L1-positive (TPS ≥1%) advanced NSCLC in China: ivonescimab vs pembrolizumab monotherapy | PFS HR 0.51; OS statistically significant (2026 announcement). | |
| LEAP-012 NCT04246177 | 3 | Mixed | Unresectable non-metastatic HCC: TACE + lenvatinib + pembrolizumab vs TACE + placebo | PFS HR 0.66; final OS HR 0.98. | |
| NADINA NCT04949113 | 3 | Positive | Resectable macroscopic stage III melanoma: two cycles neoadjuvant ipilimumab + nivolumab then surgery (adjuvant only if incomplete response) vs surgery then 12 cycles adjuvant nivolumab | 12-month EFS 83.7% vs 57.2%; HR 0.32. | |
| TiNivo-2 NCT04987203 | 3 | Negative | Advanced RCC after progression on a PD-1/PD-L1 inhibitor: tivozanib + nivolumab vs tivozanib | PFS HR 1.10; no benefit from nivolumab rechallenge. | |
| CARES-310 NCT03764293 | 3 | Positive | First-line unresectable HCC: camrelizumab + rivoceranib vs sorafenib | OS 23.8 vs 15.2 months, HR 0.62. | |
| EV-302 / KEYNOTE-A39 NCT04223856 | 3 | Positive | First-line advanced urothelial cancer: enfortumab vedotin + pembrolizumab vs platinum chemotherapy | OS HR 0.47. | |
| IND.227 / KEYNOTE-483 NCT02784171 | 3 | Positive | Unresectable pleural mesothelioma, first line: pembrolizumab + platinum-pemetrexed vs platinum-pemetrexed | OS 17.3 vs 16.1 months, HR 0.79; ORR 52% vs 29%. | |
| KEYNOTE-671 NCT03425643 | 3 | Positive | Resectable stage II-IIIB NSCLC: neoadjuvant pembrolizumab + chemotherapy then adjuvant pembrolizumab vs placebo | EFS HR 0.58; OS HR 0.72. | |
| KEYNOTE-859 NCT03675737 | 3 | Positive | First-line HER2-negative advanced gastric/GEJ adenocarcinoma: pembrolizumab + chemotherapy vs placebo + chemotherapy | OS HR 0.78 (all); CPS ≥10 OS 15.7 vs 11.8 months (HR 0.65). | |
| KEYNOTE-966 NCT04003636 | 3 | Positive | First-line advanced biliary tract cancer: gemcitabine-cisplatin + pembrolizumab vs + placebo | OS 12.7 vs 10.9 months, HR 0.83. | |
| KEYNOTE-A18 / ENGOT-cx11 / GOG-3047 NCT04221945 | 3 | Positive | Newly diagnosed high-risk locally advanced cervical cancer (FIGO 2014 IB2-IIB node-positive or III-IVA): pembrolizumab + cisplatin chemoradiation + brachytherapy, then pembrolizumab, vs chemoradiation | PFS HR 0.70; 36-month OS 82.6% vs 74.8% (HR 0.67). | |
| NRG-GY018 / KEYNOTE-868 NCT03914612 | 3 | Positive | Advanced or recurrent endometrial cancer: pembrolizumab + carboplatin-paclitaxel then pembrolizumab maintenance vs chemotherapy, analysed by MMR status | PFS HR 0.30 (dMMR), 0.54 (pMMR). | |
| RUBY / ENGOT-EN6 / GOG-3031 NCT03981796 | 3 | Positive | Primary advanced (stage III-IV) or first recurrent endometrial cancer: dostarlimab + carboplatin-paclitaxel, then dostarlimab up to 3 years, vs chemotherapy | OS 44.6 vs 28.2 months overall (HR 0.69); dMMR PFS HR 0.28. | |
| SWOG S1826 NCT03907488 | 3 | Positive | Untreated stage III-IV classical Hodgkin lymphoma, age ≥12: nivolumab + AVD vs brentuximab vedotin + AVD | 2-year PFS 92% vs 83%, HR 0.45. | |
| ASTRUM-005 NCT04063163 | 3 | Positive | First-line ES-SCLC: serplulimab + carboplatin-etoposide vs placebo + carboplatin-etoposide | OS 15.4 vs 10.9 months, HR 0.63. | |
| CheckMate 816 NCT02998528 | 3 | Positive | Resectable stage IB-IIIA NSCLC: neoadjuvant nivolumab + platinum chemotherapy (3 cycles) vs chemotherapy | EFS HR 0.63; OS HR 0.72. | |
| COSMIC-313 NCT03937219 | 3 | Mixed | Untreated intermediate/poor-risk clear-cell RCC: cabozantinib + nivolumab + ipilimumab vs nivolumab + ipilimumab | PFS HR 0.73; OS HR 1.02 (no benefit). | |
| LEAP-002 NCT03713593 | 3 | Negative | First-line unresectable HCC: lenvatinib + pembrolizumab vs lenvatinib | OS HR 0.84, not significant. | |
| RATIONALE-306 NCT03783442 | 3 | Positive | First-line advanced oesophageal squamous cell carcinoma: tislelizumab + platinum chemotherapy vs placebo + chemotherapy | OS 17.2 vs 10.6 months (HR 0.66); PD-L1 ≥1% OS 16.8 vs 9.6 months. | |
| CheckMate 274 NCT02632409 | 3 | Positive | High-risk muscle-invasive urothelial carcinoma after radical surgery: adjuvant nivolumab 1 year vs placebo | DFS HR 0.70; OS HR 0.83 (ITT), median 75 vs 50.1 months. | |
| CheckMate 577 NCT02743494 | 3 | Mixed | Resected oesophageal/GEJ cancer with residual disease after neoadjuvant chemoradiation: adjuvant nivolumab 1 year vs placebo | DFS 22.4 vs 11.0 months (HR 0.69); OS 51.7 vs 35.3 months (HR 0.85, NS). | |
| CheckMate 648 NCT03143153 | 3 | Positive | First-line advanced oesophageal squamous cell carcinoma: nivolumab + chemotherapy, or nivolumab + ipilimumab (chemotherapy-free), vs chemotherapy | PD-L1 ≥1%: OS 15.4 vs 9.1 months (nivo + chemo, HR 0.54); 13.7 vs 9.1 months (nivo + ipi, HR 0.64). | |
| CLEAR (KEYNOTE-581) NCT02811861 | 3 | Positive | Untreated advanced clear-cell RCC: lenvatinib + pembrolizumab vs sunitinib (and lenvatinib + everolimus arm) | PFS 23.9 vs 9.2 months (HR 0.39); OS HR 0.79. | |
| DREAMseq (ECOG-ACRIN EA6134) NCT02224781 | 3 | Positive | Untreated BRAF V600 metastatic melanoma: nivolumab + ipilimumab then dabrafenib + trametinib at progression, vs the reverse sequence | 2-year OS 71.8% vs 51.5%. | |
| EMPOWER-Cervical 1 / GOG-3016 / ENGOT-cx9 NCT03257267 | 3 | Positive | Recurrent cervical cancer after first-line platinum: cemiplimab vs single-agent chemotherapy | OS 12.0 vs 8.5 months (HR 0.69). | |
| ESCORT-1st NCT03691090 | 3 | Positive | First-line advanced oesophageal squamous cell carcinoma (China): camrelizumab + paclitaxel/cisplatin vs placebo + chemotherapy | OS 15.3 vs 12.0 months, HR 0.70. | |
| JUPITER-02 NCT03581786 | 3 | Positive | Untreated recurrent or metastatic nasopharyngeal carcinoma: toripalimab + gemcitabine-cisplatin vs chemotherapy | PFS HR 0.52; OS HR 0.63. | |
| KEYNOTE-564 NCT03142334 | 3 | Positive | Clear-cell RCC at intermediate-high or high risk of recurrence after nephrectomy (or M1 NED): adjuvant pembrolizumab 1 year vs placebo | DFS HR 0.72; OS HR 0.62. | |
| KEYNOTE-716 NCT03553836 | 3 | Positive | Resected stage IIB or IIC melanoma: adjuvant pembrolizumab 1 year vs placebo | RFS and DMFS improved; 5-year benefit sustained (ESMO 2025). | |
| KEYNOTE-775 / Study 309 NCT03517449 | 3 | Positive | Advanced endometrial cancer after platinum: lenvatinib + pembrolizumab vs doxorubicin or weekly paclitaxel | OS 18.3 vs 11.4 months (HR 0.62). | |
| KEYNOTE-826 NCT03635567 | 3 | Positive | Persistent, recurrent, or metastatic cervical cancer, first line: pembrolizumab + platinum-paclitaxel ± bevacizumab vs placebo + chemotherapy ± bevacizumab | OS 26.4 vs 16.8 months (HR 0.63), all comers. | |
| CheckMate 548 & CheckMate 143 & CheckMate 498 NCT02667587 | 3 | Negative | Glioblastoma: nivolumab added to standard therapy (newly diagnosed, MGMT-methylated CM548; MGMT-unmethylated vs temozolomide CM498) and nivolumab vs bevacizumab at recurrence (CM143) | No OS benefit in any of the three trials. | |
| CheckMate 649 NCT02872116 | 3 | Positive | First-line HER2-negative advanced gastric/GEJ/oesophageal adenocarcinoma: nivolumab + chemotherapy vs chemotherapy | CPS ≥5: OS 14.4 vs 11.1 months (HR 0.71); 5-year OS 16% vs 6%. | |
| CheckMate 743 NCT02899299 | 3 | Positive | Unresectable pleural mesothelioma, first line: nivolumab + ipilimumab vs platinum-pemetrexed | OS 18.1 vs 14.1 months, HR 0.74; 5-year OS 14% vs 6%. | |
| CheckMate 9ER NCT03141177 | 3 | Positive | Untreated advanced clear-cell RCC: nivolumab + cabozantinib vs sunitinib | PFS HR 0.51; OS HR 0.77 at ~4 years (46.5 vs 36.0 months). | |
| IMpassion131 NCT03125902 | 3 | Negative | First-line metastatic TNBC: atezolizumab + paclitaxel vs paclitaxel | PFS HR 0.82 (not significant); OS trend unfavourable; US indication withdrawn 2021. | |
| KEYNOTE-177 NCT02563002 | 3 | Positive | First-line MSI-H/dMMR metastatic colorectal cancer: pembrolizumab vs investigator-choice chemotherapy | PFS 16.5 vs 8.2 months (HR 0.60); 5-year OS 54.8%, median OS 77.5 months. | |
| KEYNOTE-204 NCT02684292 | 3 | Positive | Relapsed/refractory classical Hodgkin lymphoma: pembrolizumab vs brentuximab vedotin | PFS 13.2 vs 8.3 months, HR 0.65. | |
| KEYNOTE-355 NCT02819518 | 3 | Positive | First-line metastatic TNBC: pembrolizumab + chemotherapy vs chemotherapy | OS HR 0.73 in CPS ≥10. | |
| KEYNOTE-522 NCT03036488 | 3 | Positive | Early-stage (II-III) TNBC: pembrolizumab + chemotherapy before surgery, pembrolizumab after | EFS HR 0.63; OS HR 0.66 (5-year); 7-year OS 85.1% vs 77.2%. | |
| KEYNOTE-590 NCT03189719 | 3 | Positive | First-line advanced oesophageal cancer (squamous and adenocarcinoma) and Siewert I GEJ: pembrolizumab + cisplatin/5-FU vs chemotherapy | OS 12.4 vs 9.8 months (HR 0.73); 5-year OS HR 0.72. | |
| KEYNOTE-048 NCT02358031 | 3 | Positive | Untreated recurrent or metastatic HNSCC: pembrolizumab alone, pembrolizumab + platinum/5-FU, or cetuximab + platinum/5-FU (EXTREME) | OS 14.9 vs 10.7 months (CPS ≥20, monotherapy); 13.0 vs 10.7 (all, with chemotherapy). | |
| KEYNOTE-426 NCT02853331 | 3 | Positive | Untreated advanced clear-cell RCC: pembrolizumab + axitinib vs sunitinib | OS HR 0.84 final (47.2 vs 40.8 months); PFS HR 0.69. | |
| CheckMate 214 NCT02231749 | 3 | Positive | Untreated advanced clear-cell RCC: nivolumab + ipilimumab vs sunitinib | 8-year OS HR 0.72 (ITT), 0.69 (intermediate/poor risk). | |
| CheckMate 141 NCT02105636 | 3 | Positive | Platinum-refractory recurrent or metastatic HNSCC: nivolumab vs investigator's choice (methotrexate, docetaxel, or cetuximab) | OS 7.5 vs 5.1 months; HR 0.70. | |
| KEYNOTE-024 & KEYNOTE-189 NCT02142738 | 3 | Positive | First-line metastatic NSCLC without EGFR/ALK: pembrolizumab alone (PD-L1 TPS ≥50%, KEYNOTE-024) or pembrolizumab + platinum-pemetrexed (any PD-L1, non-squamous, KEYNOTE-189) | 5-year OS 31.9% vs 16.3% (024); 19.4% vs 11.3% (189). | |
| CheckMate 067 NCT01844505 | 3 | Positive | Untreated advanced melanoma: nivolumab + ipilimumab vs nivolumab vs ipilimumab | 10-year OS 43% vs 37% vs 19%. | |
| KEYNOTE-006 NCT01866319 | 3 | Positive | Advanced melanoma, ≤1 prior systemic therapy: pembrolizumab (two schedules) vs ipilimumab | 10-year OS 34.0% vs 23.6%. | |
| AHOD2131 (COG / NCTN) NCT05675410 | 3 | Recruiting | Newly diagnosed stage I-II classical Hodgkin lymphoma, age 5-60: standard therapy vs brentuximab vedotin + nivolumab (response-adapted), with or without radiation | ||
| ASCENT-05 / OptimICE-RD (AFT-65, GBG 119, NSABP B-63) NCT05633654 | 3 | Active | Stage II–III TNBC with residual invasive disease after neoadjuvant therapy and surgery: adjuvant sacituzumab govitecan + pembrolizumab vs pembrolizumab ± capecitabine | ||
| LiGeR-HN1 NCT06525220 | 3 | Recruiting | Untreated PD-L1-positive recurrent or metastatic HNSCC: petosemtamab + pembrolizumab vs pembrolizumab | ||
| OptimICE-pCR (A012103) NCT05812807 | 3 | Recruiting | Stage II-III TNBC with pathologic complete response after KEYNOTE-522 regimen: adjuvant pembrolizumab vs observation | ||
| PRISM-MEL-301 NCT06112314 | 3 | Recruiting | Untreated HLA-A*02:01-positive advanced cutaneous melanoma: brenetafusp + nivolumab vs nivolumab-based regimens | ||
| SCARLET (SWOG S2212) NCT05929768 | 3 | Recruiting | Stage II-III TNBC: anthracycline-free carboplatin/docetaxel + pembrolizumab vs KEYNOTE-522 regimen | ||
| TROPION-Breast03 NCT05629585 | 3 | Active | Stage I–III TNBC with residual invasive disease after neoadjuvant therapy: adjuvant Dato-DXd ± durvalumab vs investigator's choice (capecitabine, pembrolizumab, or both) | ||
| TROPION-Breast05 NCT06103864 | 3 | Recruiting | First-line PD-L1+ metastatic TNBC: Dato-DXd ± durvalumab vs pembrolizumab + chemotherapy | ||
| RELATIVITY-047 NCT03470922 | 2/3 | Positive | Untreated unresectable or metastatic melanoma: nivolumab + relatlimab (fixed dose) vs nivolumab | PFS HR 0.75; median OS 51.0 vs 34.1 months. | |
| FORTIFI-HN01 NCT06788990 | 2/3 | Recruiting | Untreated PD-L1-positive, HPV-negative recurrent or metastatic HNSCC: ficerafusp alfa + pembrolizumab vs pembrolizumab | ||
| AZUR-1 NCT05723770 | 2 | Positive | Untreated stage II/III dMMR/MSI-H locally advanced rectal cancer: dostarlimab monotherapy for 6 months, no surgery or radiation if complete response | Primary endpoint (sustained cCR at 12 months) met; rates pending congress presentation. | |
| NICHE-2 NCT03026140 | 2 | Positive | Locally advanced (mostly stage III) dMMR colon cancer: 4 weeks of neoadjuvant nivolumab + one dose ipilimumab, then surgery | pCR 68%, major pathologic response 95%; 3-year DFS 100%. | |
| SWOG S1801 NCT03698019 | 2 | Positive | Resectable stage IIIB-IV melanoma: three doses of pembrolizumab before surgery then 15 after, vs 18 doses after surgery | 2-year EFS 72% vs 49%; HR 0.58. | |
| FMT plus pembrolizumab in anti-PD-1-refractory melanoma (Pittsburgh) NCT03341143 | 2 | Completed | Metastatic melanoma with primary resistance to anti-PD-1: single colonoscopic FMT from a durable responder donor, then pembrolizumab | 6 of 15 patients with clinical benefit (3 objective responses). | |
| CheckMate 205 NCT02181738 | 2 | Positive | Relapsed/refractory classical Hodgkin lymphoma after autologous transplant: nivolumab (cohorts A-C); cohort D nivolumab-AVD frontline | ORR 69%. | |
| MIMic-01: healthy-donor FMT plus anti-PD-1, first-line melanoma NCT03772899 | 1 | Completed | Untreated advanced melanoma: oral capsule FMT from healthy donors one week before, then with, nivolumab or pembrolizumab | ORR 65% (13 of 20), 4 complete responses; no FMT-related serious adverse events. |
Resistance routes that involve this target
Unaddressed routes → Immune evasion · PD-1 / PD-L1 checkpoint inhibitors
Loss of antigen presentation (B2M, HLA, JAK1/2)
Frequency: Acquired resistance in melanoma: ~25% JAK/B2M
Mutations in B2M or HLA class I stop tumour cells displaying antigen; JAK1/2 loss removes interferon responsiveness (and PD-L1 induction).
Countermeasures · 1
- NK-cell and CAR-based approaches that do not need MHC; T-cell engagers
Immune evasion · PD-1 / PD-L1 checkpoint inhibitors
Immune-desert / excluded tumours
No pre-existing T-cell infiltrate (cold tumour) or T cells held at the margin by TGF-β and stroma.
Countermeasures · 3
- Radiation, oncolytic viruses, ADC + IO to prime
- Personalised neoantigen vaccines to supply T cells
- TIL therapy after PD-1 failure
Bypass · PD-1 / PD-L1 checkpoint inhibitors
Alternative checkpoints (LAG-3, TIM-3, TIGIT)
Exhausted T cells co-express other inhibitory receptors.
Countermeasures · 1
- Relatlimab + nivolumab (LAG-3) works; TIGIT combinations failed
Immune evasion · PD-1 / PD-L1 checkpoint inhibitors
Immunosuppressive myeloid cells and VEGF
MDSCs, M2 macrophages, and VEGF suppress T-cell function and dendritic-cell maturation.
Countermeasures · 1
- PD-1 + VEGF blockade; PD-1×VEGF bispecifics
Antigen loss · PD-1 / PD-L1 checkpoint inhibitors
Loss of neoantigens / low TMB
Immunoediting removes the clones that carried immunogenic mutations.
Countermeasures · 1
- Vaccines against shared antigens (KRAS)
Pathways where it is a node
Pathway-to-drug matrix →- Cold tumours: immune deserts and exclusionNode: Inflamed → PD-1 response · 6 druggable nodes
Tumours come in three immune weathers: inflamed (T cells inside, checkpoint drugs work), excluded (T cells stuck at the edge), and desert (no T cells at all). Most common cancers are excluded or desert, and turning them 'hot' is the central problem of immunotherapy.
Which nodes have drugs → - Complement in cancerNode: CD8 T cells suppressed · 3 druggable nodes
Complement is a cascade of blood proteins that punches holes in things marked by antibodies and calls in inflammatory cells. Therapeutic antibodies such as rituximab use it to kill cancer cells; tumours defend themselves with shields (CD46, CD55, CD59), and the cascade's own by-products (C5a) can recruit the myeloid cells that protect the tumour.
Which nodes have drugs → - Fibroblast activation, desmoplasia & matrix stiffnessNode: T-cell exclusion · 4 druggable nodes
Tumours recruit the body's repair cells, fibroblasts, and keep them in wound-healing mode forever. The scar tissue they lay down (desmoplasia) squeezes blood vessels shut, walls out immune cells, stiffens the tissue in a way that itself tells cancer cells to grow, and is why pancreatic cancer is so hard to treat.
Which nodes have drugs → - Glutamine addictionNode: T cells starved · 4 druggable nodes
After glucose, glutamine is the tumour's favourite food. It feeds the energy cycle, donates nitrogen for making DNA letters, and makes the antioxidant glutathione. MYC- and KRAS-driven cancers eat so much of it that they starve the T cells next door.
Which nodes have drugs → - Microbiome–tumour interactionsNode: Immunotherapy response · 1 druggable nodes
The bacteria in the gut, and even inside tumours, influence whether cancer starts and whether immunotherapy works. Transplanting stool from responders has made some non-responders respond.
Which nodes have drugs → - Mismatch repair & microsatellite instabilityNode: Checkpoint-inhibitor response · 2 druggable nodes
After DNA is copied, a proofreading crew fixes the letters the polymerase got wrong. Lose it and the genome fills with thousands of small errors, especially in repetitive stretches (microsatellites). Those errors make abnormal proteins that the immune system can see, which is why immunotherapy works so well in these cancers.
Which nodes have drugs → - Nutrient competition & metabolic immunosuppressionNode: T-cell / NK dysfunction · 4 druggable nodes
Tumours and immune cells eat from the same plate. Cancer cells hoard glucose and glutamine, dump lactate and acid, and burn tryptophan and arginine into by-products that paralyse T cells. The tumour wins the food fight, and the immune system loses before it has fired a shot.
Which nodes have drugs → - Oncogenic virusesNode: Viral antigens → IO response · 3 druggable nodes
About one cancer in eight worldwide is caused by a virus. HPV, hepatitis B and C, Epstein-Barr, HTLV-1, KSHV and Merkel cell polyomavirus each hijack the same brakes cancer normally has to mutate, which is why vaccines against HPV and HBV are among the most effective anti-cancer drugs ever made.
Which nodes have drugs → - PD-1 / PD-L1 immune checkpoint & T-cell activationNode: PD-1 on T cell · 4 druggable nodes
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.
Which nodes have drugs → - T-cell exhaustionNode: PD-1, LAG-3, TIM-3, TIGIT · 3 druggable nodes
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.
Which nodes have drugs → - The cancer-immunity cycleNode: 7 Killing (PD-1 brake) · 3 druggable nodes
Seven steps the immune system must complete to kill a tumour: release of antigens, pick-up by dendritic cells, priming of T cells in lymph nodes, travel, entry into the tumour, recognition, and killing. Every immunotherapy pushes on one step; every escape blocks one.
Which nodes have drugs → - Tumour microenvironment (TME)Node: Exhausted CD8 T cells (PD-1) · 5 druggable nodes
A tumour is not just cancer cells. It is a neighbourhood of fibroblasts, immune cells, blood vessels, nerves, and scaffolding that the cancer recruits and corrupts, and that decides whether drugs and immune cells can get in.
Which nodes have drugs →
Companion diagnostics and assays
Assay registry →| Assay | Platform | Cut-off | Gates |
|---|---|---|---|
| PD-L1 IHC 22C3 pharmDx Agilent (Dako) · FDA CDx 2015 | IHC | TPS at least 1% or at least 50% (NSCLC); CPS at least 1 (head and neck, oesophageal, gastric); CPS at least 10 (TNBC, gastric first line); CPS at least 1 (cervical) | |
| PD-L1 IHC 28-8 pharmDx Agilent (Dako) · FDA CDx 2020 | IHC | TC at least 1% (nivolumab plus ipilimumab, first-line NSCLC) | |
| FoundationOne CDx Foundation Medicine (Roche) · FDA CDx 2017 | NGS tissue | Per companion claim: EGFR, ALK, BRAF V600, ERBB2 amplification, KRAS wild-type, BRCA1/2 and HRR genes, PIK3CA, MET exon 14, RET, FGFR2 fusions, IDH1, NTRK fusions; MSI-high; TMB at least 10 mutations per megabase | |
| VENTANA MMR RxDx Panel Roche Diagnostics · FDA CDx 2021 | IHC | Loss of nuclear expression of any mismatch-repair protein in tumour cells (dostarlimab, endometrial cancer) | |
| MSI by PCR (Promega MSI Analysis System and equivalents) Promega and others · LDT | PCR | Instability at two or more of five markers (MSI-high); NGS panels report MSI from hundreds of loci | |
| Tumour mutational burden (FoundationOne CDx and equivalents) Foundation Medicine and others · FDA CDx 2020 | NGS tissue | At least 10 mutations per megabase (pembrolizumab, tumour-agnostic, KEYNOTE-158) |
Preclinical models
All models →| Cell line | Identifiers | Why it is used |
|---|---|---|
| MC38 Mus musculus | CVCL_B288 | Mouse colon; PD-1 responsive. |
| CT26 Mus musculus | CVCL_7254 | Mouse colon; partially responsive. |
| B16-F10 Mus musculus | CVCL_0159 | Mouse melanoma; PD-1 refractory unless combined. |
| 4T1 Mus musculus | CVCL_0125 | Mouse breast; refractory, metastatic. |
| LL/2 Mus musculus | CVCL_4358 | Lewis lung carcinoma; refractory. |
| EMT6 Mus musculus | CVCL_1923 | Mouse breast; responsive. |
| YUMMER1.7 Mus musculus | CVCL_A2AX | UV-mutagenised Braf/Pten melanoma; responsive. |
| KPC-derived lines | not resolved | Pancreatic; immune-excluded and refractory. |
Mouse models
- KP lung and KPC pancreas (Kras G12D; Trp53) DuPage et al., Nat Protoc 2009
PDX and organoid banks
Syngeneic lines are the only immunocompetent option for human checkpoint biology but carry far higher mutation burden than most human tumours, and the human antibodies do not bind mouse PD-1, so surrogate antibodies are used.
Open questions
All open questions →- 01
How long should checkpoint inhibitors be given: two years, one year, or until a ctDNA or imaging signal says stop?
clinicalpayerWhy unresolved. Trials fixed two years by convention; long-term CheckMate 067 and KEYNOTE-006 data show durable remissions after stopping, and the cost and toxicity of unnecessary years are large.
What would answer it. Randomised stop-versus-continue trials with ctDNA-guided arms, powered for overall survival.
Source: CheckMate 067 ten-year follow-up, NEJM 2025 - 02
What actually turns an immune-desert tumour into one that responds to PD-1 blockade?
basicresearchWhy unresolved. Most patients have primary resistance: no T-cell infiltrate or T cells excluded by stroma. Radiation, oncolytic viruses, ADCs and vaccines each prime in some models, but no combination has produced a reliable conversion in people.
What would answer it. Randomised combination trials with mandatory on-treatment biopsies linking immune-infiltration change to survival, and mechanistic studies of exclusion drivers such as TGF-beta and CXCL12.
Source: Topalian et al., NEJM 2012 - 03
For which cancers should neoadjuvant immunotherapy replace surgery-first, and can pathological response replace long-term endpoints?
clinicalclinicWhy unresolved. NADINA, CheckMate 816, NICHE-2 and KEYNOTE-522 show deep pathological responses, but regulators still want event-free or overall survival and surgeons want to know who can safely have less surgery.
What would answer it. Validation of pathological complete response as a surrogate across tumour types and de-escalation trials that omit or reduce surgery in complete responders.
Source: NADINA, NEJM 2024
Ideas and companies
Ideas that involve this target · 14
An abbreviated approval path for follow-on antibodies within a validated classAn advance market commitment for PD-1 biosimilars for lower-income countriesBiomarker-directed first-line quadruplets in gastric cancerBRAF/MEK plus PD-1 blockade as standard for BRAF-mutant anaplastic thyroid cancerCD8 PET to stop or switch immunotherapy earlyConfirm ultra-low-dose immunotherapy so it can be afforded where most patients liveExtended-interval immunotherapy: give checkpoint inhibitors every 8-12 weeks once stableGive immunotherapy in the morningMaking microsatellite-stable colorectal cancer immunotherapy-responsiveMicrobiome transplant as a routine immunotherapy adjunctRandomised trials of stopping immunotherapy after one year versus continuingRegionally delivered mesothelin CAR-T with PD-1 blockadeShorter exclusivity for later-in-class drugs without added benefitWhat actually holds T cells at the tumour border?
Key papers and the live literature
Preprints →- CheckMate 067 at ten years: half of melanoma patients treated with nivolumab plus ipilimumab were alive a decade later · New England Journal of Medicine 2025
- CheckMate 067 at ten years: nivolumab plus ipilimumab produces long-term survival in half of patients with advanced melanoma · New England Journal of Medicine 2025
- HARMONi-2: ivonescimab, a PD-1 x VEGF bispecific, beats pembrolizumab head-to-head in PD-L1-positive lung cancer · The Lancet 2025
- EV-302: enfortumab vedotin plus pembrolizumab replaces chemotherapy as first treatment for advanced bladder cancer · New England Journal of Medicine 2024
- KEYNOTE-942: a personalised mRNA cancer vaccine plus pembrolizumab after melanoma surgery · The Lancet 2024
- KEYNOTE-A18: pembrolizumab with chemoradiotherapy for locally advanced cervical cancer · The Lancet 2024
- NADINA: two doses of ipilimumab plus nivolumab before surgery beat a year of nivolumab after surgery in stage III melanoma · New England Journal of Medicine 2024
- NICHE-2: a month of nivolumab and ipilimumab before surgery clears mismatch-repair-deficient colon cancer in most patients · New England Journal of Medicine 2024
- NICHE-2: a single dose of ipilimumab and two of nivolumab before surgery clears dMMR colon cancer in most patients · New England Journal of Medicine 2024
- SWOG S1826: nivolumab plus AVD chemotherapy versus brentuximab-AVD for advanced Hodgkin lymphoma in adolescents and adults · New England Journal of Medicine 2024
- Rojas 2023: a personalised mRNA vaccine trained T cells against each patient's pancreatic cancer, and those who responded stayed cancer-free longer · Nature 2023
- RUBY: dostarlimab with chemotherapy for advanced or recurrent endometrial cancer · New England Journal of Medicine 2023
- Cercek 2022: six months of dostarlimab alone made rectal cancer disappear in every patient with mismatch-repair deficiency · New England Journal of Medicine 2022
- CheckMate 816: three cycles of nivolumab plus chemotherapy before lung cancer surgery · New England Journal of Medicine 2022
- Dostarlimab alone cures mismatch-repair-deficient rectal cancer without surgery or radiotherapy · New England Journal of Medicine 2022
- KEYNOTE-522: adding pembrolizumab before and after surgery in early triple-negative breast cancer · New England Journal of Medicine 2022
- RELATIVITY-047: relatlimab plus nivolumab, the first LAG-3 checkpoint combination, in untreated advanced melanoma · New England Journal of Medicine 2022
- ASCO 2021 guideline: how to recognise and manage the immune-related side effects of checkpoint inhibitors · Journal of Clinical Oncology 2021
- CheckMate 649: nivolumab plus chemotherapy as first treatment for advanced gastric, gastro-oesophageal junction and oesophageal adenocarcinoma · The Lancet 2021
- CLEAR: lenvatinib plus pembrolizumab versus sunitinib as first treatment for advanced kidney cancer · New England Journal of Medicine 2021
- KEYNOTE-564: a year of pembrolizumab after kidney cancer surgery · New England Journal of Medicine 2021
- KEYNOTE-177: pembrolizumab instead of chemotherapy as first treatment for mismatch-repair-deficient metastatic colorectal cancer · New England Journal of Medicine 2020
- KEYNOTE-048: pembrolizumab, alone or with chemotherapy, as first treatment for recurrent or metastatic head and neck cancer · The Lancet 2019
- KEYNOTE-189: pembrolizumab plus chemotherapy as first treatment for non-squamous lung cancer without a driver mutation · New England Journal of Medicine 2018
- Le 2017: mismatch-repair deficiency predicts response to PD-1 blockade across twelve tumour types, leading to the first tissue-agnostic drug approval · Science 2017
- Le 2015: PD-1 blockade works in tumours with mismatch-repair deficiency, whatever the organ · New England Journal of Medicine 2015
- Topalian 2012: the first large trial of a PD-1 antibody shows durable responses across melanoma, lung and kidney cancer · New England Journal of Medicine 2012
- Iwai and Honjo: tumours use PD-L1 to escape T cells, and blocking it restores attack · PNAS 2002
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