Protein lactylation: molecular mechanisms underlying lactate-driven tumorigenesis and cancer progression

Lactylation, a recently identified post-translational modification, has reshaped our understanding of lactate from a metabolic byproduct to a central regulator of tumor biology. Accumulating evidence reveals that lactate-driven lactylation orchestrates metabolic reprogramming, epigenetic remodeling, immune evasion, metastasis, and therapeutic resistance, thereby fueling malignant progression. Beyond histones, diverse non-histone substrates further expand its regulatory network across cancer signaling pathways. We highlight the crosstalk between lactylation and other modifications, its role in tumor heterogeneity, and the therapeutic opportunities arising from targeting this pathway. These insights establish lactylation as both a hallmark and a potential vulnerability of cancer, opening new avenues for precision oncology.