文献类型：期刊文献

英文题名：Metabolic-epigenetic crosstalk in lung cancer: Glycolytic reprogramming and lactylation-driven macrophage polarization

作者：Wang, Caixia[1,2];Liu, Shiqing[2,3];Fan, Junshun[1];Liu, Lu[3];Sun, Yanqing[3,4,5]

第一作者：王彩霞

通信作者：Sun, YQ[1]

机构：[1]Gansu Univ Chinese Med, Coll Integrated Chinese & Western Med, Lanzhou 730030, Peoples R China;[2]Gansu Univ Chinese Med, Expt & Training Teaching Ctr, Lanzhou 730000, Gansu, Peoples R China;[3]Gansu Univ Chinese Med, Clin Coll 1, Lanzhou 730000, Gansu, Peoples R China;[4]Gansu Prov Hosp, Dept Hematol, Lanzhou 730000, Gansu, Peoples R China;[5]Gansu Prov Peoples Hosp, 204 Donggang West Rd, Lanzhou 730000, Gansu, Peoples R China

第一机构：甘肃中医药大学

通信机构：[1]corresponding author), Gansu Prov Peoples Hosp, 204 Donggang West Rd, Lanzhou 730000, Gansu, Peoples R China.

年份：2026

卷号：286

外文期刊名：PATHOLOGY RESEARCH AND PRACTICE

收录：;WOS:【SCI-EXPANDED(收录号:WOS:001785418000001)】；

基金：This study was supported by the Gansu Provincial People's Hospital Outstanding Master's/Doctoral Student Cultivation Program (No. ZX-62000001-2022-678) , the Gansu Provincial Department of Education Excellent Graduate "Innovation Star" Project (No. 2021KCYB-4) , and 2025 Undergraduate Research Innovation and Entrepreneurship Project of First Clinical College of Gansu University of Chinese Medicine (No. yIkc-202502) .

语种：英文

外文关键词：Metabolic reprogramming; Lactate; Lactylation modification; Lung cancer; Tumor-Associated Macrophages

摘要：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 metabolicepigenetic inhibitors-advances crucial for ushering in a new era of precision immunotherapy anchored in the synergy of metabolic intervention and epigenetic remodeling.