FOSL2 Regulates PD-L1 and Modulates Hormone Therapy Response Heterogeneity

The response to androgen-targeted therapy in prostate cancer (PCa) is highly heterogeneous. While previous studies have primarily concentrated on tumor cell-intrinsic signaling changes, the tumor microenvironment, particularly the interactions between tumor-infiltrating lymphocytes (TILs) 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 (NADT), we employed publicly available clinical datasets, in vitro T cell-PCa cell co-culture systems, and murine xenograft models to investigate this interplay. We found treatment-related dynamic change in TILs 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 it 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 PCa. 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 PCa.