Metabolic-epigenetic crosstalk in lung cancer: Glycolytic reprogramming and lactylation-driven macrophage...

Lung cancer remains the leading cause of cancer-related mortality worldwide, with persistent clinical challenges driven by immune evasion, disease recurrence, and therapeutic resistance. A core mechanism underlying these obstacles is metabolic-epigenetic rewiring within TME, fueled by aberrant aerobic glycolysis (the Warburg effect) and subsequent lactate accumulation. Once regarded merely as a glycolytic byproduct, lactate has been redefined as a dual-functional signaling metabolite-serving as both a metabolic substrate and a key regulator of gene expression-following the discovery of histone lactylation, a novel epigenetic modification that directly links cellular metabolism to chromatin states.TAMs, the most abundant immune cell population in the TME, are polarized toward immunosuppressive M2 phenotypes via two interrelated lactate-dependent pathways: (i) monocarboxylate transporter 4 (MCT4)-mediated lactate efflux induces extracellular acidification, activating acid-sensing G-protein-coupled receptors to promote M2-like differentiation; and (ii) intracellular lactate acts as a metabolic signal to induce lactylation of both histone and non-histone proteins, establishing an epigenetic network that stabilizes M2 polarization. While the dynamic crosstalk between metabolism and epigenetics in the TME is increasingly recognized, prior studies have largely examined these axes in isolation, leaving their synergistic contribution to immune evasion poorly elucidated.Herein, we synthesize current knowledge to propose a unified framework directly linking glycolytic reprogramming to lactylation, establishing the latter as a critical metabolic- epigenetic bridge in lung cancer pathogenesis. We systematically dissect the enzymatic networks governing lactylation dynamics-including writers, readers, and erasers--and evaluate their roles in TAM polarization and tumor progression. Furthermore, we assess therapeutic strategies targeting this axis- inhibition, MCT1/4 blockade, lactyltransferase interference) as promising approaches to reverse immunosuppression and restore tumor sensitivity to PD-1/PD-L1 checkpoint inhibitors. Looking ahead, we emphasize the necessity of resolving TME spatiotemporal heterogeneity via single-cell multi-omics and developing dual metabolic-epigenetic inhibitors-advances crucial for ushering in a new era of precision immunotherapy anchored in the synergy of metabolic intervention and epigenetic remodeling.