The long non-coding RNA UGDH-AS1 encodes an NK-cell-inhibiting micropeptide in triple-negative breast cancers.

NK cells are important for the anti-tumour immune response for their potential to kill MHC class I-deficient tumor cells, but they often become dysfunctional in the immune-hostile tumour microenvironment. Here, using single-cell RNA sequencing, we identify an NK cell subpopulation that is specific to triple-negative breast cancers (TNBC) subtype, characterised by the expression of the long non-coding RNA UGDH-AS1. In these NK cells, UGDH-AS1 encodes the micropeptide, NKSM, which renders these NK cells dysfunctional due to the loss of their activation program, which leads to cancer progression. Conditional NKSM knock-in into NK cells of mice results in NK cell deactivation and increased growth of transplanted tumours. Targeted NKSM therapy effectively reduces tumor growth in TNBC mouse models. We find that UGDH-AS1(+) NK cells are shaped by the tumor microenvironment (TME). Following upregulation by the TGF-β signaling pathway, NKSM binds to Myc, inhibiting its ERK1/2-mediated phosphorylation at Serine 62 and thus reducing its stability. Decreased Myc activity results in deregulation of T-bet, a key protein involved in NK cell function, which leads to NK cell deactivation. Our study thus provides mechanistic insight int NK cell dysfunctionality in TNBC and lays down the proof of principle for an NK-cell-targeting TNBC immunotherapy.