{"entity":{"id":"t-cell-exhaustion","kind":"pathway","name":"T-cell exhaustion","aka":[],"tldr":"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.","summary":"Chronic TCR stimulation with insufficient help drives a stepwise programme: TCF1+ progenitor-exhausted cells (stem-like, lymph-node and tertiary-lymphoid-structure resident, PD-1 intermediate) self-renew and give rise to transitory effector-like cells and then terminally exhausted cells (PD-1 high, TIM-3, CD39, CD101) with poor IL-2/TNF/IFN-γ production, driven by NFAT without AP-1, TOX and NR4A, and fixed by DNMT3A-dependent de novo methylation ('epigenetic scarring'). PD-1 blockade expands the progenitor pool and its transitory progeny rather than reviving terminal cells; response correlates with the size of the TCF1+ reservoir and with CD28 co-stimulation (PD-1 dephosphorylates CD28). Co-inhibitory receptors partition: LAG-3 (MHC-II, FGL1) blocked by relatlimab; TIGIT (CD155) by tiragolumab (mixed phase 3 results); TIM-3 (galectin-9, CEACAM1) by sabatolimab. CAR-T cells exhaust the same way (CD8 CAR-T with c-Jun overexpression or TET2 loss resist it); interval rests and PD-1 knockout are engineering countermeasures.","asOf":"2026-09-09","wikipedia":"https://en.wikipedia.org/wiki/T_cell_exhaustion","links":[{"label":"Wherry & Kurachi, Molecular and cellular insights into T cell exhaustion (Nat Rev Immunol 2015)","url":"https://doi.org/10.1038/nri3862"}],"tags":["mechanism","mechanics-atlas"],"related":[],"cancers":[],"sections":[],"technologies":["checkpoint-inhibitor","car-t","til-therapy","cytokine-therapy","armored-car"],"targets":["pd1","pdl1","lag3","tigit","tim3","ctla4","cd19"],"drugs":["pembrolizumab","nivolumab","relatlimab-nivolumab","fianlimab","tiragolumab","nogapendekin-alfa","bempegaldesleukin"],"companies":[],"institutions":[],"pathways":["pd1-checkpoint","antigen-presentation-immunoediting","cancer-immunity-cycle","epigenetic-reprogramming"],"terms":["tils","cold-vs-hot","irae","avoiding-immune-destruction"],"trials":[],"people":[],"bottlenecks":["b-immunotherapy-response"],"keyPapers":["paper-wherry-nat-rev-immunol"],"journals":[],"dependsOn":[],"notes":[],"analogy":"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.","nodes":[{"id":"chronic","label":"Chronic antigen, no help","x":12,"y":15},{"id":"tcf1","label":"TCF1+ progenitor (stem-like)","x":40,"y":15},{"id":"trans","label":"Transitory effector","x":68,"y":15},{"id":"term","label":"Terminally exhausted","x":90,"y":40},{"id":"tox","label":"TOX, NR4A, NFAT","x":40,"y":45},{"id":"epi","label":"DNMT3A epigenetic scar","x":68,"y":45},{"id":"brakes","label":"PD-1, LAG-3, TIM-3, TIGIT","x":12,"y":50,"targetId":"pd1"},{"id":"kill","label":"Cytokines, killing","x":40,"y":82},{"id":"block","label":"Checkpoint blockade","x":12,"y":82,"targetId":"lag3"},{"id":"cart","label":"CAR-T exhaustion","x":78,"y":82,"targetId":"cd19"}],"edges":[{"from":"chronic","to":"tcf1","type":"activates"},{"from":"tcf1","to":"trans","type":"activates"},{"from":"trans","to":"term","type":"activates"},{"from":"chronic","to":"tox","type":"activates"},{"from":"tox","to":"brakes","type":"activates"},{"from":"tox","to":"epi","type":"activates"},{"from":"epi","to":"term","type":"activates"},{"from":"brakes","to":"kill","type":"inhibits"},{"from":"trans","to":"kill","type":"activates"},{"from":"block","to":"brakes","type":"inhibits"},{"from":"block","to":"tcf1","type":"activates"},{"from":"chronic","to":"cart","type":"activates"}],"interventions":["Anti-PD-1/PD-L1; combinations with anti-LAG-3 (relatlimab-nivolumab, fianlimab) and anti-TIGIT (tiragolumab, mixed results)","Earlier use (neoadjuvant) when the TCF1+ reservoir is larger; IL-2 variants and IL-15 superagonists to expand progenitors","CAR-T engineering: c-Jun overexpression, TET2/DNMT3A editing, transient rest, PD-1 knockout","Epigenetic drugs to reverse scarring (preclinical)"]},"route":"/pathways/t-cell-exhaustion/","neighbours":{"technology":[{"id":"armored-car","kind":"technology","name":"Armoured, logic-gated & next-gen CARs","route":"/technologies/armored-car/"},{"id":"car-t","kind":"technology","name":"CAR-T cell therapy","route":"/technologies/car-t/"},{"id":"cytokine-therapy","kind":"technology","name":"Cytokines & engineered cytokines","route":"/technologies/cytokine-therapy/"},{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"},{"id":"til-therapy","kind":"technology","name":"TIL therapy","route":"/technologies/til-therapy/"}],"target":[{"id":"cd19","kind":"target","name":"CD19","route":"/targets/cd19/"},{"id":"ctla4","kind":"target","name":"CTLA-4","route":"/targets/ctla4/"},{"id":"lgals9","kind":"target","name":"Galectin-9 (LGALS9)","route":"/targets/lgals9/"},{"id":"lag3","kind":"target","name":"LAG-3","route":"/targets/lag3/"},{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"},{"id":"pdl1","kind":"target","name":"PD-L1","route":"/targets/pdl1/"},{"id":"tigit","kind":"target","name":"TIGIT","route":"/targets/tigit/"},{"id":"tim3","kind":"target","name":"TIM-3","route":"/targets/tim3/"},{"id":"tox","kind":"target","name":"TOX","route":"/targets/tox/"}],"drug":[{"id":"bempegaldesleukin","kind":"drug","name":"Bempegaldesleukin","route":"/drugs/bempegaldesleukin/"},{"id":"fianlimab","kind":"drug","name":"Fianlimab","route":"/drugs/fianlimab/"},{"id":"nivolumab","kind":"drug","name":"Nivolumab","route":"/drugs/nivolumab/"},{"id":"nogapendekin-alfa","kind":"drug","name":"Nogapendekin alfa inbakicept","route":"/drugs/nogapendekin-alfa/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"},{"id":"relatlimab-nivolumab","kind":"drug","name":"Relatlimab + nivolumab","route":"/drugs/relatlimab-nivolumab/"},{"id":"tiragolumab","kind":"drug","name":"Tiragolumab","route":"/drugs/tiragolumab/"}],"pathway":[{"id":"antigen-presentation-immunoediting","kind":"pathway","name":"Antigen presentation & immune editing","route":"/pathways/antigen-presentation-immunoediting/"},{"id":"epigenetic-reprogramming","kind":"pathway","name":"Epigenetic reprogramming","route":"/pathways/epigenetic-reprogramming/"},{"id":"pd1-checkpoint","kind":"pathway","name":"PD-1 / PD-L1 immune checkpoint & T-cell activation","route":"/pathways/pd1-checkpoint/"},{"id":"cancer-immunity-cycle","kind":"pathway","name":"The cancer-immunity cycle","route":"/pathways/cancer-immunity-cycle/"}],"term":[{"id":"avoiding-immune-destruction","kind":"term","name":"Hallmark: avoiding immune destruction","route":"/terms/avoiding-immune-destruction/"},{"id":"cold-vs-hot","kind":"term","name":"Hot vs cold tumours","route":"/terms/cold-vs-hot/"},{"id":"immune-surveillance-immunoediting","kind":"term","name":"Immune surveillance and cancer immunoediting","route":"/terms/immune-surveillance-immunoediting/"},{"id":"irae","kind":"term","name":"Immune-related adverse events (irAEs)","route":"/terms/irae/"},{"id":"tils","kind":"term","name":"Tumour-infiltrating lymphocytes (TILs)","route":"/terms/tils/"}],"bottleneck":[{"id":"b-immunotherapy-response","kind":"bottleneck","name":"No one can predict who responds to immunotherapy","route":"/bottlenecks/b-immunotherapy-response/"}],"paper":[{"id":"paper-skoulidis-kras-co-mutation-subsets-cancer-discov-2015","kind":"paper","name":"Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities","route":"/key-papers/paper-skoulidis-kras-co-mutation-subsets-cancer-discov-2015/"},{"id":"paper-ricciuti-stk11-keap1-kras-immunotherapy-jto-2022","kind":"paper","name":"Diminished efficacy of programmed death-(ligand)1 inhibition in STK11- and KEAP1-mutant lung adenocarcinoma is affected by KRAS mutation status","route":"/key-papers/paper-ricciuti-stk11-keap1-kras-immunotherapy-jto-2022/"},{"id":"paper-arbour-kras-co-mutation-outcomes-ccr-2018","kind":"paper","name":"Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer","route":"/key-papers/paper-arbour-kras-co-mutation-outcomes-ccr-2018/"},{"id":"paper-wherry-nat-rev-immunol","kind":"paper","name":"Molecular and cellular insights into T cell exhaustion","route":"/key-papers/paper-wherry-nat-rev-immunol/"},{"id":"paper-kras-nsclc-cancer-discov-2018","kind":"paper","name":"STK11/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS -Mutant Lung Adenocarcinoma","route":"/key-papers/paper-kras-nsclc-cancer-discov-2018/"},{"id":"paper-schoenfeld-smarca4-alterations-lung-ccr-2020","kind":"paper","name":"The genomic landscape of SMARCA4 alterations and associations with outcomes in patients with lung cancer","route":"/key-papers/paper-schoenfeld-smarca4-alterations-lung-ccr-2020/"}],"cancer":[{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}],"biomarker":[{"id":"stk11-keap1-loss","kind":"biomarker","name":"STK11 or KEAP1 loss in KRAS-mutant lung adenocarcinoma","route":"/biomarkers/stk11-keap1-loss/"}]}}