Histone lactylation-driven intratumoral IGFBP2+ NK cells promote tumor immune evasion.

Natural killer (NK) cells are known for their cytotoxic and regulatory functions in immune responses. Here, we identify a subset of insulin-like growth factor binding protein 2 (IGFBP2)+ NK cells enriched in liver cancer, exhibiting impaired cytotoxicity and correlating with poor prognosis in patients with liver cancer. The hypoxic tumor microenvironment induces IGFBP2 expression in NK cells. Mechanistically, hypoxia drives lactate accumulation in intratumoral NK cells, promoting histone H3 lysine 18 lactylation (H3K18La) at the IGFBP2 promoter and enhancing IGFBP2 transcription. NK cell-secreted IGFBP2 inhibits the expression of stress-related activating immune ligands (MICA/B and ecto-CRT) on neighboring tumor cells, thereby reducing their sensitivity to cytotoxic immune cells and promoting immune evasion. Antibody-mediated IGFBP2 blockade increases tumor cell sensitivity to cytotoxic immune cells. Additionally, IGFBP2 blockade synergizes with immune checkpoint therapy to enhance anti-tumor efficacy in liver cancer models.