Pharmacological inhibition of histone Lactylation enhances immunotherapy efficacy in gastrointestinal cancers.

Although immunotherapy has reshaped the treatment landscape for gastrointestinal (GI) malignancies, durable clinical benefit is achieved in only a subset of patients, largely due to the emergence of immune resistance. Accumulating evidence highlights histone lactylation, an epigenetic modification driven by excessive lactate accumulation, as a pivotal mediator linking tumor metabolism to immune suppression. By reprogramming transcriptional networks within the tumor microenvironment, histone lactylation skews macrophages toward an immunosuppressive phenotype and compromises T-cell effector function, thereby facilitating tumor immune escape. In metabolically active GI tumors with pronounced lactate production, aberrant histone lactylation contributes to the establishment of a profoundly immunosuppressive niche that undermines responses to immune checkpoint inhibitors. Targeting lactylation-related pathways has therefore gained attention as a novel therapeutic avenue, with the potential to restore antitumor immune activity, enhance cytotoxic lymphocyte function, and sensitize tumors to immunotherapy. This article summarizes current understanding of the crosstalk between lactate metabolism, histone lactylation, and immune regulation, and highlights therapeutic approaches targeting this epigenetic axis to enhance immunotherapy efficacy in GI cancers.