Abstract
Dysregulation of lactate metabolism is a hallmark of multiple pathologies, including cancer, which coordinates metabolic reprogramming and malignant progression. Lactylation, a lactate‑derived post‑translational modification, is a key regulator of tumor cell adaptation, aggressive behavior and immune escape. This modification mechanism links lactate accumulation to carcinogenic signaling and epigenetic dysregulation, providing novel insights into cancer pathogenesis. The present review summarizes the roles of lactylation in tumor microenvironment (TME) remodeling, therapeutic resistance and immunomodulation, and outlines the challenges to clinical translation. Lactate drives the lactylation of histone and non‑histone proteins, and alters chromatin structure and transcriptional programs to maintain tumorigenesis. In the TME, lactylation modulates the phenotypes of stromal cells (such as cancer‑associated fibroblasts) and immune cells (including macrophages and T cells), forming an immunosuppressive niche. Lactylation can also polarize macrophages towards a tumor‑promoting state, inhibit CD8+ T cells and upregulate immune checkpoints. Clinically, lactylation is associated with chemotherapy resistance (such as paclitaxel in breast cancer) and a poor prognosis, highlighting its usefulness as a biomarker. Notably, therapeutic strategies targeting lactate synthesis (such as lactate dehydrogenase A inhibitors), lactate transport (for example, monocarboxylate transporter 1/4 blockers) or lactase (such as histone lactate transferase) have shown promise in preclinical models. In conclusion, lactylation promotes tumor progression while also providing a viable therapeutic target. Deciphering its environment‑dependent mechanisms, particularly its interactions with immune checkpoints and metabolic vulnerabilities, may advance precision oncology. Validating biomarkers and therapies centered on lactylation is a key frontier in improving clinical outcomes.