Extracellular CD44 lactylation impairs CD8+ T cell function in KRAS-mutant colorectal cancer.

Kirsten rat sarcoma (KRAS) mutations are key drivers of oncogenesis and therapy resistance in colorectal cancer (CRC), yet the underlying molecular mechanisms and effective targeted therapies are currently limited. Here we identify thyroid hormone receptor interactor 6 (TRIP6) phosphorylation as a critical mechanism of immune evasion in KRAS-mutant (KRAS/MT) CRC. In KRAS wild-type CRC cells, unphosphorylated TRIP6 binds to KDM1A, repressing enolase 2 (ENO2) expression via H3K9me1/H3K9me2 accumulation and limiting glycolysis. In KRAS/MT CRC cells, ERK1/ERK2-mediated phosphorylation of TRIP6 disrupts this interaction, enhancing ENO2-driven glycolysis and lactate production. Elevated extracellular lactate promotes CD44 lactylation on CD8+ T cells, impairs hyaluronan binding and AKT signalling, and ultimately suppresses anti-tumour immunity. Blocking TRIP6 phosphorylation with the peptide mouse PT6 restores T cell function and improves response to anti-PD-1 therapy in preclinical models. Collectively, our findings reveal a new mechanism of immune evasion in KRAS/MT CRC and suggest that targeting the TRIP6–ENO2–CD44 lactylation axis could be a promising strategy to overcome resistance to immunotherapy. TRIP6 phosphorylation triggers a signalling cascade that promotes glycolysis in KRAS-mutant colorectal cancer cells. The resulting lactate accumulation drives extracellular lactylation of CD44 on CD8⁺ T cells, thereby compromising their anti-tumour activity.