Lactate and lactylation in cancer: metabolic regulation, immune modulation, and therapeutic opportunities

Lactate has emerged from being viewed as a glycolytic byproduct to a central metabolic and signaling hub that coordinates tumor evolution and therapeutic adaptation. This review integrates current evidence on how lactate production, transport, and accumulation reshape cancer biology, with particular emphasis on the lactate-lactylation axis. In tumors, lactate is generated not only by malignant cells through aerobic glycolysis, hypoxia-driven metabolic rewiring, and glutamine-derived carbon flow, but also by stromal cells, immune cells, adipocytes, and tumor-associated microbiota. Through monocarboxylate transporter-mediated shuttling, lactate supports metabolic symbiosis, extracellular acidification, matrix remodeling, angiogenesis, invasion, and immune escape. Beyond these metabolic and signaling functions, lactate acts as a substrate for lysine lactylation, linking altered metabolism to epigenetic and post-translational regulation. Histone and nonhistone lactylation, governed by emerging writers, erasers, and putative readers, regulates transcription, DNA damage repair, cancer stemness, ferroptosis resistance, immune checkpoint expression, and resistance to chemotherapy, radiotherapy, targeted therapy, and immunotherapy. We further discuss the biomarker potential of lactate-related enzymes, transporters, site-specific lactylation marks, and therapeutic strategies targeting lactate production, transport, sensing, depletion, and lactylation machinery. A deeper understanding of lactate flux and lactylation-dependent vulnerabilities may enable biomarker-guided combinations that integrate metabolic intervention, epigenetic modulation, and immuno-oncology for precision cancer therapy. © 2026 The Pathological Society of Great Britain and Ireland.