PRMT5 deficiency in myeloid cells reprograms macrophages to enhance antitumor immunity and synergizes with anti-PD-L1 therapy.

BACKGROUND: Arginine methyltransferase protein arginine methyltransferase 5 (PRMT5) plays a significant role in immune regulation, particularly within the tumor microenvironment (TME). Macrophages are crucial modulators of both innate and adaptive immune responses, and their differentiation into tumor-associated macrophages is critical in shaping the TME. Despite ongoing clinical trials of small molecule inhibitors of PRMT5 for cancer therapy, their effects on macrophages, a key component of the immune system, remain poorly understood. METHODS: A pan-cancer single-cell transcriptional analysis was initially conducted to investigate the expression of PRMT5 in tumor-infiltrating myeloid cells. Myeloid-specific deletion of Prmt5 in mice, as well as the use of a PRMT5-specific inhibitor, was performed to evaluate the impact of PRMT5 on macrophage polarization and tumor progression. Bulk and single-cell transcriptomics were employed to explore the mechanistic roles of PRMT5 in regulating lipid metabolism and macrophage polarization. Additionally, the therapeutic potential of combining Prmt5 deletion with anti-programmed death-ligand 1 (PD-L1) therapy was assessed to study its effects on antitumor immunity in vivo. RESULTS: The pan-cancer single-cell transcriptional analysis revealed that PRMT5 is highly expressed in the PPARG-macrophage subset, which correlates with poor patient survival. Myeloid-specific deletion of Prmt5 reprogrammed macrophages towards an antitumor phenotype, effectively inhibiting tumor progression. Mechanistically, PRMT5 was found to regulate lipid metabolism and drive macrophage polarization toward an anti-inflammatory state via the STAT6-PPARγ pathway, fostering an immunosuppressive TME conducive to tumor growth. Notably, Prmt5 deletion induced PD-L1 expression on myeloid cells. Combining Prmt5 deletion with anti-PD-L1 therapy significantly enhanced antitumor efficacy, demonstrating a synergistic therapeutic effect. CONCLUSIONS: These findings uncover a crucial role for PRMT5 in macrophage biology and suggest that targeting PRMT5 in myeloid cells offers a promising new approach for cancer immunotherapy. The combination of PRMT5 inhibition with anti-PD-L1 therapy may provide a potent strategy to reprogram the TME and enhance antitumor immune responses.