# NK-cell recognition: missing self & stress ligands

Source: https://onco.cc/pathways/nk-cell-recognition/  
OnCo record `nk-cell-recognition` (Pathway). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Pathway
- Last checked: 2026-09-09
- Tags: mechanism; mechanics-atlas
- 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.
- 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

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Natural_killer_cell
- Morvan & Lanier, NK cells and cancer: you can teach innate cells new tricks (Nat Rev Cancer 2016): https://doi.org/10.1038/nrc.2015.5

## Connected records

- technologies: [Allogeneic (off-the-shelf) cell therapy](https://onco.cc/technologies/allogeneic-cell-therapy/), [Bispecific antibodies](https://onco.cc/technologies/bispecific-antibody/), [CAR-NK & CAR-macrophage](https://onco.cc/technologies/car-nk-macrophage/), [Cytokines & engineered cytokines](https://onco.cc/technologies/cytokine-therapy/), [Monoclonal antibodies](https://onco.cc/technologies/monoclonal-antibody/)
- targets: [CD20](https://onco.cc/targets/cd20/), [CD38](https://onco.cc/targets/cd38/), [EGFR](https://onco.cc/targets/egfr/), [FCGR3A](https://onco.cc/targets/fcgr3a/), [HER2](https://onco.cc/targets/her2/), [PD-1](https://onco.cc/targets/pd1/), [TIGIT](https://onco.cc/targets/tigit/)
- drugs: [Cetuximab](https://onco.cc/drugs/cetuximab/), [Daratumumab](https://onco.cc/drugs/daratumumab/), [Margetuximab](https://onco.cc/drugs/margetuximab/), [Nogapendekin alfa inbakicept](https://onco.cc/drugs/nogapendekin-alfa/), [Obinutuzumab](https://onco.cc/drugs/obinutuzumab/), [Rituximab](https://onco.cc/drugs/rituximab/), [Tiragolumab](https://onco.cc/drugs/tiragolumab/), [Trastuzumab](https://onco.cc/drugs/trastuzumab/)
- pathways: [Antigen presentation & immune editing](https://onco.cc/pathways/antigen-presentation-immunoediting/), [Complement in cancer](https://onco.cc/pathways/complement-in-cancer/), [Extrinsic apoptosis (death receptors)](https://onco.cc/pathways/extrinsic-apoptosis-death-receptors/), [Intravasation & circulating tumour cells](https://onco.cc/pathways/intravasation-ctc-survival/), [TGF-β signalling](https://onco.cc/pathways/tgf-beta/), [Tumour dormancy](https://onco.cc/pathways/tumor-dormancy/)
- terms: [ADCC (antibody-dependent cellular cytotoxicity)](https://onco.cc/terms/adcc/), [BCG-unresponsive](https://onco.cc/terms/bcg-unresponsive/), [Fc engineering / effector function](https://onco.cc/terms/fc-effector/), [Hallmark: avoiding immune destruction](https://onco.cc/terms/avoiding-immune-destruction/)
- key papers: [NK cells and cancer: you can teach innate cells new tricks](https://onco.cc/key-papers/paper-morvan-nat-rev-cancer/)

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