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

## TL;DR

This study shows how the loss of PBRM1 in kidney cancer creates an environment that suppresses the immune system, and targeting IL-6 could improve cancer treatment.

## Contribution

The study identifies a novel PBRM1-KDM5C-IL6 axis that drives immunosuppression in PBRM1-deficient ccRCC.

## Key findings

- PBRM1 deficiency increases M2 tumor-associated macrophages (TAMs) and forms an immune barrier with CAFs.
- Blocking IL-6 enhances the effectiveness of anti-PD-1 therapy in PBRM1-deficient tumors.
- PBRM1 regulates TAM polarization via the KDM5C-IL6 axis.

## 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.

PBRM1 ranks as the second most commonly mutated gene in ccRCC. This study reveals that PBRM1 loss promotes an immunosuppressive microenvironment by elevating M2 TAMs via the KDM5C–IL‐6 axis. These M2 TAMs, along with CAFs, form a barrier that excludes CD8+ T cells. Targeting IL‐6 synergizes with anti‐PD1 therapy, offering a promising strategy for PBRM1‐deficient tumors.