Targeting tumor cell-intrinsic POU4F1 enhances antitumor immunity and sensitizes tumors to immunotherapy in basal-like breast cancer by modulating macrophage recruitment and polarization.
Immunosuppressive tumor microenvironment is a major driver of tumor progression and therapeutic resistance. Basal-like breast cancer (BLBC), which largely overlaps with triple-negative breast cancer, generally displays an immunosuppressive tumor microenvironment enriched with tumor-associated macrophages and other immunosuppressive cell populations. However, the driving mechanisms that establish and maintain these tumor microenvironment features remain not fully understood. This study identifies tumor cell-intrinsic POU4F1 as a key regulator of the immunosuppressive tumor microenvironment in BLBC. Tumors with high POU4F1 expression exhibited lower IFNγ-related signature and poor responses to immunotherapy. In immunocompetent 4T1 tumor-bearing mice, POU4F1 knockout led to decreased infiltration of M2-like macrophages and increased infiltration of proliferative and functional CD8+ T cells and NK cells. In-vitro assays using human immune cells demonstrated that POU4F1 directly promoted monocyte recruitment and macrophage polarization, which in turn suppressed the proliferation and effector function of tumor-specific CD8+ T cells and NK cells. Mechanistically, POU4F1 upregulated CCL2 expression through NIK-mediated activation of the non-canonical NF-κB signaling pathway, thereby promoting monocyte recruitment and immunosuppressive phenotype polarization. Genetic ablation or pharmacological targeting of POU4F1 with Bobcat339 significantly inhibited tumor growth, remodeled the tumor immune microenvironment, and synergized with anti-PD-1 therapy in mouse models and patient-derived breast cancer organoids. These findings provide mechanistic insights into how POU4F1, a BLBC-specific transcription factor, orchestrates intercellular crosstalk to establish an immunosuppressive, tumor-supportive microenvironment, and indicate that targeting POU4F1 may represent a promising therapeutic strategy for BLBCs.