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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.
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.
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.
Shares TIGIT, Nogapendekin alfa inbakicept, Hallmark: avoiding immune destruction, Tiragolumab and the tags mechanism, mechanics-atlas.
Shares Fc engineering / effector function, Complement in cancer, CAR-NK & CAR-macrophage, Monoclonal antibodies and the tags mechanism, mechanics-atlas.
Shares Tumour dormancy, TGF-β signalling, HER2 and the tags mechanism, mechanics-atlas.
Shares Tumour dormancy, Intravasation & circulating tumour cells and the tags mechanism, mechanics-atlas.
Shares ADCC (antibody-dependent cellular cytotoxicity), Cetuximab, Bispecific antibodies, Trastuzumab and the tags mechanism, mechanics-atlas.
Shares Trastuzumab, EGFR, HER2 and the tags mechanism, mechanics-atlas.
Shares Intravasation & circulating tumour cells, PD-1 and the tags mechanism, mechanics-atlas.