TNBC-Specific UGDH-AS1+ NK Cells Encode NSKM, Promoting Cancer Progression by Inhibiting NK Cells Activity

Deactivation of immune cells is a major characteristic in various malignant tumors, including breast cancer, a complex and malignant cancer. Here, using single-cell RNA sequencing, we identified UGDH-AS1+ NK cells specific to the triple-negative breast cancer(TNBC) subtype, which encode the micropeptide NKSM promoting cancer progression by inhibiting NK cell activity. NKSM was upregulated in UGDH-AS1+ NK cells and associated with TNBC-infiltrating (TINK) NK cells antitumor activity. Conditional NKSM knock-in into NK cells of mice resulted in NK cell deactivation and increased tumor growth. Targeted NKSM therapy effectively reduced tumor growth in TNBC mouse models. We found that UGDH-AS1+ NK cells are shaped by the tumor microenvironment (TME). Upregulated by the TGF-β signaling pathway, NKSM could bind to proto-oncogene c-Myc, inhibiting ERK1/2-mediated Ser62 phosphorylation and reducing its stability, thereby modulating the transcription of T-bet, a key protein involved in NK cell function, and leading to NK cell deactivation. TGF-β signaling pathway convert TINK cells into UGDH-AS1+ NK cells and targeting the expression of NKSM restrain cancer progression in TNBC.