PBRM1 Deficiency Reshapes an Immune Suppressive Microenvironment Through Epigenetic Tuning of PBRM1‐KDM5C‐IL6 Axis in ccRCC

ABSTRACT Polybromo 1 (PBRM1) ranks as the second most commonly mutated gene in clear cell renal cell carcinoma (ccRCC), while its role in immune escape remains elusive. We developed a PBRM1‐knockout mice model to perform single‐cell RNA sequencing, which demonstrated a substantial population of immunosuppressive tumor‐associated macrophages (TAMs) in the spontaneous tumor, with consistent results from an orthotopic renal tumor mice model. Multiplex immunohistochemistry of clinical samples revealed that PBRM1‐deficient tumors exhibited increased M2 TAMs in both stroma and parenchyma, while CD8 + T cells were restricted to the stroma. M2 TAMs and cancer‐associated fibroblasts (CAFs) interacted to construct a tumor immune barrier, preventing CD8 + T cell infiltration. Mechanistically, PBRM1 modulated interleukin‐6 (IL‐6) expression by recruiting lysine demethylase 5C (KDM5C), thereby orchestrating M2 polarization of TAMs. Blocking IL‐6 synergistically augmented the antitumor efficacy of anti‐PD‐1 therapy. Our findings revealed a PBRM1‐KDM5C‐IL‐6 axis that influenced antitumor immunity, indicating a potential immunotherapeutic strategy in PBRM1‐deficient ccRCC.