Lactylation in cancer: molecular mechanisms and advances in clinical study

Lysine lactylation (Kla), first described in 2019, is an emerging post-translational modification that converts lactate availability into changes in chromatin state and protein function. In cancer, where glycolysis and microenvironmental hypoxia often elevate lactate, lactylation has been linked to transcriptional reprogramming, immune modulation, cellular plasticity, and therapy resistance. Here, we synthesize current evidence across major organ systems to clarify how lactylation is generated, interpreted, and removed, and how it interacts with tumor metabolism and the tumor microenvironment. We summarize enzymatic and non-enzymatic routes to Kla formation, discuss candidate writers, erasers, and readers, and highlight recurring mechanistic patterns spanning histone and non-histone substrates, including regulation of immune-evasive signaling, ferroptosis susceptibility, DNA repair, and stress-adaptation programs. We also integrate translational considerations, outlining druggable nodes within lactate production and transport pathways and within acetyltransferase and deacylase systems, and discuss how lactylation measurements could support patient stratification, pharmacodynamic monitoring, and rational combination strategies. Finally, we identify key open questions that currently limit clinical translation, including site-level causality, cell-type and spatial attribution in patient tissues, assay specificity and quantitative stoichiometry, and the conditions under which lactylation promotes versus restrains tumor progression. Together, this framework aims to guide mechanistic studies and accelerate the development of clinically actionable lactylation-directed interventions.