FOSL2 Regulates PD-L1 and Modulates Hormone Therapy Response Heterogeneity

The response to androgen-targeted therapy in prostate cancer is highly heterogeneous. Although previous studies have primarily concentrated on tumor cell-intrinsic signaling changes, the tumor microenvironment, particularly the interactions between tumor-infiltrating lymphocytes (TIL) and tumor cells, is equally critical in shaping treatment responses. Building on our previous observations linking TILs to treatment efficacy in the context of neoadjuvant androgen deprivation therapy, we employed publicly available clinical datasets, in vitro T-cell prostate cancer cell coculture systems, and murine xenograft models to investigate this interplay. We found treatment-related dynamic changes in TIL populations, accompanied by a concordant expression pattern of FOSL2 and PD-L1. Mechanistically, FOSL2 directly bound to the PD-L1 promoter to transcriptionally upregulate PD-L1, thereby modulating T-cell infiltration and function. Importantly, in vivo results demonstrated that targeting FOSL2 enhanced the antitumor effect when combined with hormone therapy and anti-PD-L1 treatment. These findings suggest that FOSL2 may contribute to treatment response heterogeneity by shaping the tumor immune microenvironment, offering novel insights into resistance mechanisms and uncovering potential strategies to enhance the efficacy of hormone therapy in prostate cancer. IMPLICATIONS: Targeting FOSL2-mediated PD-L1 regulation offers a promising strategy to overcome immune microenvironment-mediated resistance and improve the therapeutic efficacy of androgen-targeted therapy in prostate cancer.