Non-histone protein lactylation in cancer metastasis: From metabolic reprogramming to therapeutic targeting.

Cancer metastasis remains the leading cause of cancer-related mortality, and tumor metabolic reprogramming, particularly aerobic glycolysis and lactate accumulation, is increasingly recognized as a metastatic driver. Lysine lactylation provides a direct mechanism by which lactate modifies proteins to shape tumor behavior. Although initially characterized on histones as an epigenetic mark, lactylation is now widely distributed on non-histone proteins, where it functions as a metabolism-linked post-translational modification (PTM) regulating metastatic dissemination. Non-histone lactylation promotes epithelial-mesenchymal transition (EMT) through modification of EMT transcription factors and a PRMT1-vimentin axis in triple-negative breast cancer. Lactylation enhances tumor invasion and survival by stabilizing oncoproteins via ubiquitination inhibition, reprogramming metabolic flux, and activating oncogenic transcription. PD-L1 lactylation enables immune evasion, while lactylation of DNA repair proteins confers therapy resistance. Recent findings expand resistance mechanisms to include cuproptosis evasion through MTF1 lactylation in castration-resistant prostate cancer. Positive feedback loops lock tumor cells into glycolytic, lactylation-rich states reinforcing metastasis. Both lactylation and delactylation exert context-dependent oncogenic or tumor-suppressive effects, as illustrated by PARK7, functioning as a writer in hepatocellular carcinoma yet as a delactylase promoting antitumor immunity. We synthesize how non-histone lactylation regulates the metastatic cascade using a three-tier confidence framework distinguishing fully characterized circuits from proteomic screening hits, and discuss therapeutic strategies ranging direct lactylation machinery inhibitors from indirect lactate-axis modulators. Lactylation also drives organ-specific metastatic colonization and emerges as a clinical biomarker for metastasis risk stratification. These mechanisms may reveal new opportunities for lactylation-targeted therapies, though significant challenges in selectivity, toxicity, and biomarker validation remain.