G3BP2-K76 acetylation promotes tumor immunoescape by stabilizing PD-L1 expression in colorectal cancer

Colorectal cancer (CRC) often evades immune surveillance, leading to poor responses to PD-1/PD-L1 blockade immunotherapy. The underlying mechanisms regulating PD-L1 expression remain incompletely understood. We utilized co-immunoprecipitation (Co-IP) and RNA immunoprecipitation (RIP) to investigate protein-protein and protein–RNA interactions. Western blot (WB) and quantitative PCR (qPCR) were applied to assess protein and mRNA expression levels, respectively. Immunocompetent mouse models and patient-derived CRC samples were used to evaluate clinical relevance and therapeutic targeting. We identified acetylation of G3BP2 at lysine 76 (K76) as a key regulator of PD-L1-mediated immune evasion. This modification is catalyzed by p300 and reversed by HDAC6. Acetylated G3BP2 enhances binding to PABPC1 and PD-L1 mRNA, increasing its stability and upregulating PD-L1 expression. Consequently, tumors exhibit reduced cytotoxic T lymphocyte infiltration and acquire resistance to anti-PD-L1 therapy. Elevated G3BP2-K76 acetylation was observed in immunotherapy-resistant CRC tissues and promoted tumor growth in mice. A peptide inhibitor targeting K76 acetylation (K76-pe) effectively suppressed PD-L1 expression and synergized with anti-PD-L1 treatment in vivo. G3BP2-K76 acetylation represents a critical post-translational mechanism driving immune evasion in CRC. Targeting this pathway may provide a promising strategy to overcome resistance to immunotherapy. G3BP2 acetylation at lysine 76 promotes immune evasion in colorectal cancer by enhancing its binding to PABPC1 and PD-L1 mRNA, thereby stabilizing PD-L1 expression and reducing cytotoxic T cell infiltration. This modification is mediated by p300 and reversed by HDAC6. Targeting G3BP2-K76 acetylation with a specific peptide restores anti-tumor immunity and improves response to PD-L1 blockade, highlighting its critical role in regulating immune escape and its potential as a therapeutic target.