When cancer hides MHC I, NK cells may strike back

For decades, MHC class I was seen as the marker used by T cells to detect cancer, but tumors that downregulate MHC I evade T cells while potentially exposing themselves to natural killer (NK) cells that detect 'missing self.' NK cells are inhibited by MHC I through receptors like KIRs, so loss of MHC I can lift that brake, creating a vulnerability. In practice, tumors face barriers to NK cell infiltration and can become exhausted, making responses inconsistent. Researchers are pursuing NK cell–based therapies and cytokine strategies to exploit MHC I loss, particularly in cancers resistant to checkpoint inhibitors, with the goal of turning this paradox into a new therapeutic avenue while continuing to tackle delivery and safety challenges.