USP11 regulates the tumor immune microenvironment via modulating VGLL4 ubiquitination in colorectal cancer

Colorectal cancer (CRC) progression is profoundly influenced by the tumor immune microenvironment (TME), which orchestrates the interplay between cancer cells and the host immune system. Ubiquitin-specific protease 11 (USP11), a deubiquitinating enzyme known for its role in regulating protein stability and immune signaling pathways, has recently garnered attention as a potential modulator of immune responses in various malignancies. However, the precise function and underlying mechanisms of USP11 in CRC remain largely unexplored. Our study aims to elucidate the role of USP11 in CRC by investigating its expression patterns, functional impacts on the TME, and molecular interactions. Utilizing data from large-scale genomic databases, we first demonstrated that USP11 expression is significantly downregulated in CRC tissues compared with normal counterparts, suggesting a potential tumor-suppressive and immune-modulatory role of USP11 in CRC pathogenesis. Subsequently, through a series of in vitro and in vivo experiments, including the establishment of a colitis-associated CRC mouse model in USP11 knockout mice, we found that USP11 deficiency accelerates CRC progression and promotes an immunosuppressive TME, characterized by reduced infiltration of cytotoxic CD8⁺ T lymphocytes and downregulation of MHC class I antigen processing and presentation genes. Mechanistically, we identified that USP11 interacts with key components of the immune regulatory network in CRC, modulating their stability and activity through deubiquitination. This interaction ultimately influences the balance between pro-tumor and anti-tumor immune responses within the TME. Our findings provide novel insights into the complex interplay between USP11 and the TME in CRC, suggesting that USP11 functions as a positive regulator of anti-tumor immunity and may represent a candidate worthy of further investigation for restoring anti-tumor immune responses in CRC. In conclusion, this study uncovers a previously unrecognized role of USP11 in maintaining anti-tumor immunity in CRC, whereby loss of USP11 fosters an immunosuppressive TME; these findings provide a rationale for further exploration of USP11-centered strategies in CRC immunotherapy, pending validation in clinical cohorts and mechanistic rescue studies.