Metabolic–Epigenetic Crosstalk Between Cancer Cells and Tumor-Associated Macrophages: The Lactate–Histone Lactylation Feedback Axis

Hypoxia profoundly reshapes tumor metabolism, promoting glycolytic dependence and lactate accumulation within the tumor microenvironment. Once regarded primarily as a metabolic waste product, lactate is increasingly recognized as a signaling metabolite that links metabolic adaptation to epigenetic regulation through histone lysine lactylation. This emerging mechanism may be particularly important in tumor-associated macrophages (TAMs), where lactate-rich conditions can remodel transcriptional programs and influence macrophage–cancer cell communication. Hypoxia-inducible factor (HIF)-dependent glycolysis, lactate dehydrogenase A (LDHA) activity, and monocarboxylate transporter (MCT)-mediated lactate exchange collectively establish spatial lactate gradients that may facilitate macrophage lactate uptake and histone lactylation, including H3K18la. Emerging evidence implicating p300/CBP, AARS1/AARS2, and histone deacetylases further indicates that lactylation is dynamically written and erased. Lactylation-associated macrophage states may promote immune suppression, angiogenesis, extracellular-matrix remodeling, and tumor plasticity through cytokine and growth-factor networks converging on STAT3, PI3K–AKT–mTOR, NF-κB, and HIF signaling. These reciprocal interactions support a metabolic–epigenetic circuit in which cancer-derived lactate reprograms macrophage chromatin, while altered TAM functions reinforce malignant adaptation and immune escape. This review critically examines the molecular, spatial, and functional organization of the lactate–histone lactylation axis and discusses emerging therapeutic opportunities to disrupt this bidirectional macrophage–cancer cell circuitry. The integrated feedback model is presented as a testable hypothesis: evidence for individual steps is stronger than evidence for the entire closed circuit. Redox-dependent control of glycolysis and the potential of antioxidant interventions are discussed with explicit attention to mechanistic uncertainty.