Nature子刊：吴华/李贵登/郭凌川团队揭示肿瘤免疫逃逸新机制——胞外CD44乳酸化修饰损害CD8⁺T细胞功能

Core Viewpoint - The research reveals a new mechanism of immune evasion in KRAS-mutant colorectal cancer (CRC), highlighting the potential of targeting the TRIP6–ENO2–CD44 lactylation signaling axis as a promising strategy to overcome resistance to immunotherapy [3][8]. Group 1: Research Findings - The study identifies TRIP6 phosphorylation as a key mechanism for immune evasion in KRAS-mutant CRC [6]. - In KRAS wild-type CRC cells, unphosphorylated TRIP6 binds to KDM1A, inhibiting ENO2 expression and limiting glycolysis [6]. - In KRAS-mutant CRC cells, ERK1/ERK2-mediated TRIP6 phosphorylation disrupts this interaction, enhancing glycolysis and lactate production, which leads to increased lactylation of CD44 on CD8+ T cells [6]. Group 2: Implications for Treatment - Elevated extracellular lactate levels impair CD8+ T cell function by damaging hyaluronic acid binding and AKT signaling [6]. - The research team developed a specific blocking peptide, mPT6, which restores T cell function and enhances the efficacy of PD-1 immunotherapy in preclinical models [6][8]. - The findings suggest that targeting the TRIP6–ENO2–CD44 lactylation axis could be a viable approach to address immunotherapy resistance in KRAS-mutant CRC [8].