瓦氏效应驱动肿瘤免疫微环境重塑

doi:10.6040/j.issn.1671-7554.0.2026.1033

摘要/Abstract

摘要： 肿瘤微环境(tumor microenvironment, TME)的代谢重编程是推动肿瘤恶性进展、免疫逃逸和治疗耐药的重要因素。其中,有氧糖酵解即瓦氏效应,作为肿瘤最典型的代谢特征之一,与抗肿瘤免疫之间存在双向调控关系。即使在常氧条件下,肿瘤细胞仍可异常激活糖酵解通路,通过葡萄糖竞争、乳酸积累、胞外酸化和乳酸化等代谢重塑机制,构建有利于免疫抑制的TME,从而抑制效应免疫细胞的活化、浸润和杀伤功能,同时促进调节性T细胞(regulatory T cells, Treg)、肿瘤相关巨噬细胞(tumor-associated macrophages, TAMs)和髓系来源抑制细胞(myeloid-derived suppressor cells, MDSCs)等免疫抑制性细胞的募集与功能维持,进而促进肿瘤免疫逃逸并削弱免疫治疗效果。另一方面,免疫细胞的活化、分化及稳态维持高度依赖其特定的糖代谢程序,不同免疫细胞亚群在糖代谢适应能力上的差异,显著影响TME内的免疫平衡。肿瘤糖代谢通路可与程序性死亡受体1/程序性死亡配体1(programmed cell death protein 1/programmed death-ligand 1, PD-1/PD-L1)、外核苷三磷酸二磷酸水解酶1/外-5’-核苷酸酶(ectonucleoside triphosphate diphosphohydrolase 1/ecto-5'-nucleotidase, CD39/CD73)-腺苷等经典免疫抑制通路形成正反馈调控关系,可能是免疫检查点抑制剂(immune checkpoint inhibitors, ICIs)疗效受限的重要原因之一。近年来,靶向调控肿瘤糖代谢关键分子、改善TME的代谢-免疫状态并联合免疫治疗,已成为肿瘤精准治疗领域的重要研究方向。本文系统总结肿瘤瓦氏效应的核心分子调控机制,阐述糖代谢重塑诱导免疫抑制的多种途径、不同免疫细胞亚群的糖代谢适应特征,以及糖代谢与免疫通路之间的相互作用机制;同时梳理糖代谢靶向干预策略及相关临床研究进展,分析当前研究成果向临床转化所面临的主要挑战,并结合空间多组学、细胞代谢工程等新兴技术探讨未来研究方向,以期为代谢-免疫联合治疗策略的开发及临床应用提供理论依据。

关键词: 肿瘤微环境, 糖代谢重编程, 瓦氏效应, 乳酸化修饰, 肿瘤免疫, 免疫逃逸

Abstract: Metabolic reprogramming of the tumor microenvironment(TME)is a critical driver of malignant progression, immune evasion, and therapeutic resistance in cancer. Among the most prominent metabolic alterations, aerobic glycolysis, known as the Warburg effect, engages in bidirectional crosstalk with antitumor immunity. Even under normoxic conditions, tumor cells aberrantly activate glycolytic pathways and exploit multiple remodeling mechanisms-including glucose competition, lactate accumulation, extracellular acidification, and lactylation-to establish an immunosuppressive TME. This metabolic rewiring suppresses the activation, infiltration, and cytotoxic functions of effector immune cells, while simultaneously promoting the recruitment and functional maintenance of immunosuppressive populations such as regulatory T cells(Tregs), tumor-associated macrophages(TAMs), and myeloid-derived suppressor cells(MDSCs), thereby facilitating immune evasion and attenuating the efficacy of immunotherapies. Conversely, the activation, differentiation, and homeostatic maintenance of immune cells are strictly dependent on specific glycolytic programs, and the differential metabolic adaptability among immune cell subsets profoundly influences the immune equilibrium within the TME. Accumulating evidence indicates that tumor glycolytic pathways engage in positive feedback regulatory loops with classical immunosuppressive axes, including the programmed cell death protein 1/programmed death-ligand 1(PD-1/PD-L1)and the ectonucleoside triphosphate diphosphohydrolase 1/ecto-5'-nucleotidase(CD39/CD73)-adenosine pathways, which may represent a pivotal mechanism underlying the limited efficacy of immune checkpoint inhibitors. In recent years, targeted modulation of key glycolytic molecules, improvement of the metabolic-immune landscape of the TME, and combination with immunotherapy have emerged as important research directions in precision oncology. This review systematically summarizes the core molecular regulatory mechanisms of the Warburg effect, delineates the multiple pathways through which glycolytic reprogramming induces immunosuppression, characterizes the glycolytic metabolic adaptations of distinct immune cell subsets, and elucidates the interplay between glycolytic metabolism and immune signaling pathways. Furthermore, we review glycolytic-targeted intervention strategies and relevant clinical progress, analyze the major challenges hindering clinical translation of current research findings, and discuss future directions leveraging emerging technologies such as spatial multi-omics and cell metabolic engineering, with the aim of providing a theoretical foundation for the development and clinical application of metabolism-immunity combination therapeutic strategies.

Key words: Tumor microenvironment, Glycolytic reprogramming, Warburg effect, Lactylation, Tumor immunity, Immune evasion

中图分类号:

R730.2

褚颖辰,朱文洁,高鹏. 瓦氏效应驱动肿瘤免疫微环境重塑[J]. 山东大学学报 (医学版), 2026, 64(10): 104-116.

CHU Yingchen, ZHU Wenjie, GAO Peng. Warburg effect drives remodeling of the tumor immune microenvironment[J]. Journal of Shandong University (Health Sciences), 2026, 64(10): 104-116.

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