Lactate-driven lactylation and acidification reshape tumor immunity in the TME

This is a narrative review that examines the role of lactate in the tumor microenvironment (TME), focusing on three interconnected mechanisms: lactate accumulation, protein lactylation (an epigenetic modification), and TME acidification. The authors synthesize evidence from in vitro and preclinical studies involving tumor cells and immune cells such as macrophages, T cells, and dendritic cells. They propose that elevated lactate levels drive lactylation of histones and other proteins, altering gene expression in immune cells and promoting an immunosuppressive milieu. Concurrently, acidification of the TME impairs T cell function and enhances macrophage polarization toward a pro-tumor phenotype. The review highlights how these processes collectively contribute to immune evasion and tumor progression. However, the authors do not report a systematic search strategy, pooled data, or quantitative synthesis. Limitations include the lack of clinical trial data, absence of comparator groups, and no formal assessment of bias. The review is primarily hypothesis-generating and underscores the need for translational studies to validate these mechanisms in human cancers. For clinicians, the findings suggest that targeting lactate metabolism or lactylation could represent a novel immunotherapeutic strategy, but no direct practice recommendations can be drawn from this narrative synthesis alone.