Histone lactylation in gastrointestinal cancers: developing immunotherapeutic drugs targeting epigenetics

Gastrointestinal cancers (GICs) remain a major global health burden due to their aggressive nature, therapeutic resistance, and immunosuppressive tumor microenvironment (TME). Histone lactylation, a novel epigenetic modification driven by tumor-derived lactate, has emerged as a key mediator linking metabolic reprogramming to gene expression and immune regulation. In GICs, aberrant lactylation contributes to M2 macrophage polarization, increased PD-L1 expression, and diminished cytotoxic immune cell infiltration, all of which are associated with poor prognosis and resistance to immunotherapy. Targeting histone lactylation-related enzymes-such as p300, SIRT2, and LDHA-or interfering with lactate metabolism offers promising avenues to reshape the TME and enhance responses to immune checkpoint blockade. This review highlights the mechanistic underpinnings and immunological consequences of histone lactylation in GICs and discusses emerging therapeutic strategies that leverage this epigenetic axis to improve cancer immunotherapy outcomes.