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

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.