Lactylation in cancer: a new frontier in metabolic-epigenetic regulation and clinical practice

Yihan Zhang, Lan Chen, Yaxi Qin, Yuxing Wang, Xi Liu, Minghui Zhang, Jing Tang

The discovery of lysine lactylation (Kla) redefines lactate from a passive glycolytic by-product into a bioactive metabolic mediator that directly links cellular metabolism to epigenetic regulation. This emerging post-translational modification dynamically alters histone and non-histone proteins, thereby reconfiguring gene expression programs and immune responses within the tumor microenvironment (TME). It consequently promotes core malignant phenotypes including uncontrolled proliferation, epithelial-mesenchymal transition (EMT), metastatic dissemination, and resistance to chemotherapy, radiotherapy, and immune checkpoint blockade. Specific epigenetic signatures, notably histone H3K18la and H4K12la marks, serve as transcriptional anchors for oncogenic pathways across multiple cancer types. Multi-omics analyses have further yielded Kla-associated gene profiles with the potential to refine prognostic stratification and drug-target identification. These findings establish Kla as a central axis in tumor-associated metabolic-epigenetic crosstalk. Effective clinical application of KLAsKla biomarkers requires resolving technical detection limits and addressing the spatiotemporal heterogeneity that currently constrains machine learning-based prognostic models. Overcoming these bottlenecks is contingent upon leveraging advanced technologies such as single-cell multi-omics and spatial transcriptomics. This review characterizes the emerging roles of Kla in tumor metabolism, providing a framework for its future application as a diagnostic and therapeutic cornerstone in precision oncology.