{"entity":{"id":"nk-cell-recognition","kind":"pathway","name":"NK-cell recognition: missing self & stress ligands","aka":[],"tldr":"Natural killer cells patrol for cells that have lost their identity papers (MHC-I) or that display stress flags. Cancers that hide from T cells by dropping MHC-I become visible to NK cells, unless they also shed the stress flags, wrap themselves in a second inhibitory badge (HLA-E), or soak the neighbourhood in TGF-β.","summary":"NK activation integrates inhibitory signals from KIRs and NKG2A (binding classical HLA-A/B/C and HLA-E respectively; 'missing self' when MHC-I is lost) against activating signals from NKG2D (MICA/B, ULBP1-6, induced by DNA damage and oncogenes), DNAM-1 (CD155, CD112), NKp30 (B7-H6), NKp46, and CD16 (FcγRIIIa, mediating ADCC by IgG1 antibodies such as trastuzumab and cetuximab). Killing is by perforin/granzyme and death ligands; IFN-γ recruits and licenses the adaptive response. Tumour escape: proteolytic shedding of MICA/B (ADAM10/17), HLA-E upregulation engaging NKG2A (monalizumab, mixed results), TIGIT and PVRIG competing with DNAM-1 for CD155, TGF-β and adenosine downregulating NKG2D, platelet cloaking of CTCs. NK cells are central to clearing circulating tumour cells and dormant cells and to controlling MHC-I-negative escape variants after checkpoint or CAR-T therapy. Therapeutics: CAR-NK (cord blood, iPSC-derived, off the shelf, low CRS), NK engagers (CD16×target), IL-15 superagonists (nogapendekin alfa approved in NMIBC), anti-NKG2A, antibody afucosylation to boost ADCC.","asOf":"2026-09-09","wikipedia":"https://en.wikipedia.org/wiki/Natural_killer_cell","links":[{"label":"Morvan & Lanier, NK cells and cancer: you can teach innate cells new tricks (Nat Rev Cancer 2016)","url":"https://doi.org/10.1038/nrc.2015.5"}],"tags":["mechanism","mechanics-atlas"],"related":[],"cancers":[],"sections":[],"technologies":["car-nk-macrophage","monoclonal-antibody","cytokine-therapy","allogeneic-cell-therapy","bispecific-antibody"],"targets":["tigit","her2","egfr","cd20","cd38","pd1"],"drugs":["trastuzumab","cetuximab","rituximab","obinutuzumab","margetuximab","daratumumab","nogapendekin-alfa","tiragolumab"],"companies":[],"institutions":[],"pathways":["antigen-presentation-immunoediting","extrinsic-apoptosis-death-receptors","tgf-beta","intravasation-ctc-survival","tumor-dormancy"],"terms":["adcc","fc-effector","bcg-unresponsive","avoiding-immune-destruction"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-morvan-nat-rev-cancer"],"journals":[],"dependsOn":[],"notes":[],"analogy":"Guards who stop anyone not wearing a staff badge (MHC-I) or anyone visibly panicking (stress ligands). Cancer's trick against T cells (throwing away the badge) makes it conspicuous to these guards, so successful tumours also learn to stop panicking, borrow a visitor badge (HLA-E) and bribe the guards with TGF-β.","nodes":[{"id":"mhc","label":"MHC-I → KIR (inhibit)","x":12,"y":15},{"id":"hlae","label":"HLA-E → NKG2A (inhibit)","x":12,"y":45},{"id":"stress","label":"MICA/B, ULBP → NKG2D","x":12,"y":75},{"id":"nk","label":"NK cell decision","x":45,"y":45},{"id":"cd16","label":"CD16 ← IgG1 antibody (ADCC)","x":45,"y":12,"targetId":"her2"},{"id":"tigit","label":"TIGIT vs DNAM-1 (CD155)","x":45,"y":80,"targetId":"tigit"},{"id":"kill","label":"Perforin, granzyme, IFN-γ","x":78,"y":30},{"id":"shed","label":"MICA shedding, TGF-β","x":78,"y":65},{"id":"carnk","label":"CAR-NK, IL-15, NK engagers","x":92,"y":90}],"edges":[{"from":"mhc","to":"nk","type":"inhibits"},{"from":"hlae","to":"nk","type":"inhibits"},{"from":"stress","to":"nk","type":"activates"},{"from":"cd16","to":"nk","type":"activates"},{"from":"tigit","to":"nk","type":"inhibits"},{"from":"nk","to":"kill","type":"activates"},{"from":"shed","to":"stress","type":"inhibits"},{"from":"shed","to":"nk","type":"inhibits"},{"from":"carnk","to":"nk","type":"activates"}],"interventions":["IgG1 antibodies (trastuzumab, cetuximab, rituximab) recruit NK ADCC; afucosylated antibodies (obinutuzumab, margetuximab) bind CD16 harder","IL-15 superagonist nogapendekin alfa (BCG-unresponsive NMIBC); CAR-NK and NK engagers in trials","Anti-NKG2A (monalizumab) and anti-TIGIT (tiragolumab) release inhibitory checks, with mixed phase 3 results","NK-based therapies address MHC-I-loss escape from T-cell therapies"]},"route":"/pathways/nk-cell-recognition/","neighbours":{"technology":[{"id":"allogeneic-cell-therapy","kind":"technology","name":"Allogeneic (off-the-shelf) cell therapy","route":"/technologies/allogeneic-cell-therapy/"},{"id":"bispecific-antibody","kind":"technology","name":"Bispecific antibodies","route":"/technologies/bispecific-antibody/"},{"id":"car-nk-macrophage","kind":"technology","name":"CAR-NK & CAR-macrophage","route":"/technologies/car-nk-macrophage/"},{"id":"cytokine-therapy","kind":"technology","name":"Cytokines & engineered cytokines","route":"/technologies/cytokine-therapy/"},{"id":"monoclonal-antibody","kind":"technology","name":"Monoclonal antibodies","route":"/technologies/monoclonal-antibody/"}],"target":[{"id":"cd20","kind":"target","name":"CD20","route":"/targets/cd20/"},{"id":"cd38","kind":"target","name":"CD38","route":"/targets/cd38/"},{"id":"egfr","kind":"target","name":"EGFR","route":"/targets/egfr/"},{"id":"fcgr3a","kind":"target","name":"FCGR3A","route":"/targets/fcgr3a/"},{"id":"her2","kind":"target","name":"HER2","route":"/targets/her2/"},{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"},{"id":"tigit","kind":"target","name":"TIGIT","route":"/targets/tigit/"}],"drug":[{"id":"cetuximab","kind":"drug","name":"Cetuximab","route":"/drugs/cetuximab/"},{"id":"daratumumab","kind":"drug","name":"Daratumumab","route":"/drugs/daratumumab/"},{"id":"margetuximab","kind":"drug","name":"Margetuximab","route":"/drugs/margetuximab/"},{"id":"nogapendekin-alfa","kind":"drug","name":"Nogapendekin alfa inbakicept","route":"/drugs/nogapendekin-alfa/"},{"id":"obinutuzumab","kind":"drug","name":"Obinutuzumab","route":"/drugs/obinutuzumab/"},{"id":"rituximab","kind":"drug","name":"Rituximab","route":"/drugs/rituximab/"},{"id":"tiragolumab","kind":"drug","name":"Tiragolumab","route":"/drugs/tiragolumab/"},{"id":"trastuzumab","kind":"drug","name":"Trastuzumab","route":"/drugs/trastuzumab/"}],"pathway":[{"id":"antigen-presentation-immunoediting","kind":"pathway","name":"Antigen presentation & immune editing","route":"/pathways/antigen-presentation-immunoediting/"},{"id":"complement-in-cancer","kind":"pathway","name":"Complement in cancer","route":"/pathways/complement-in-cancer/"},{"id":"extrinsic-apoptosis-death-receptors","kind":"pathway","name":"Extrinsic apoptosis (death receptors)","route":"/pathways/extrinsic-apoptosis-death-receptors/"},{"id":"intravasation-ctc-survival","kind":"pathway","name":"Intravasation & circulating tumour cells","route":"/pathways/intravasation-ctc-survival/"},{"id":"tgf-beta","kind":"pathway","name":"TGF-β signalling","route":"/pathways/tgf-beta/"},{"id":"tumor-dormancy","kind":"pathway","name":"Tumour dormancy","route":"/pathways/tumor-dormancy/"}],"term":[{"id":"adcc","kind":"term","name":"ADCC (antibody-dependent cellular cytotoxicity)","route":"/terms/adcc/"},{"id":"bcg-unresponsive","kind":"term","name":"BCG-unresponsive","route":"/terms/bcg-unresponsive/"},{"id":"fc-effector","kind":"term","name":"Fc engineering / effector function","route":"/terms/fc-effector/"},{"id":"avoiding-immune-destruction","kind":"term","name":"Hallmark: avoiding immune destruction","route":"/terms/avoiding-immune-destruction/"}],"paper":[{"id":"paper-morvan-nat-rev-cancer","kind":"paper","name":"NK cells and cancer: you can teach innate cells new tricks","route":"/key-papers/paper-morvan-nat-rev-cancer/"}]}}