P3FI-90 activates innate immune responses in triple-negative breast cancer.

Immunotherapy has emerged as a promising therapeutic option for cancer management, but its applicability in patients with triple–negative breast cancer (TNBC) is limited by the low efficacy due to the immunosuppressive tumor microenvironment (TME). Here, we identify lysine demethylase 3B (KDM3B) as an essential mediator of immune evasion in TNBC. KDM3B expression is negatively correlated with cytotoxic T lymphocyte (CTL) infiltration. Genetic or pharmacologic inhibition of KDM3B facilitates the recruitment and activation of CD8+ T cells, thereby suppressing tumor growth in TNBC mouse models. Mechanistically, KDM3B targets SHP1 by reducing H3K9me2 levels at its promoter. Suppression of KDM3B attenuates SHP1–mediated STING inactivation, which triggers robust type Ⅰ IFN responses. Strikingly, both KDM3B depletion and treatment with the KDM3B–selective inhibitor P3FI–90 significantly suppresses tumor progression and mitigates resistance to immune checkpoint blockade (ICB) therapy. Taken together, these findings establish KDM3B as a key regulator of immune escape, and targeting KDM3B represents a promising strategy to augment the efficacy of immunotherapy for TNBC.