HPK1 Dysregulation‐Associated NK Cell Dysfunction and Defective Expansion Promotes Metastatic Melanoma Progression

Abstract Distant metastasis, the leading cause of cancer death, is efficiently kept in check by immune surveillance. Studies have uncovered peripheral natural killer (NK) cells as key antimetastatic effectors and their dysregulation during metastasis. However, the molecular mechanism governing NK cell dysfunction links to metastasis remains elusive. Herein, MAP4K1 encoding HPK1 is aberrantly overexpressed in dysfunctional NK cells in the periphery and the metastatic site. Conditional HPK1 overexpression in NK cells suffices to exacerbate melanoma lung metastasis but not primary tumor growth. Conversely, MAP4K1 ‐deficient mice are resistant to metastasis and further protected by combined immune‐checkpoint inhibitors. Mechanistically, HPK1 restrains NK cell cytotoxicity and expansion via activating receptors. Likewise, HPK1 limits human NK cell activation and associates with melanoma NK cell dysfunction couples to TGF‐β1 and patient response to immune checkpoint therapy. Thus, HPK1 is an intracellular checkpoint controlling NK‐target cell responses, which is dysregulated and hijacked by tumors during metastatic progression.