乳酸调控肿瘤恶性进程的研究进展

doi:10.19401/j.cnki.1007-3639.2025.11.009

摘要/Abstract

摘要：

恶性肿瘤作为全球公共卫生领域的重大挑战，迫切需要创新诊疗策略。乳酸作为肿瘤细胞糖酵解的重要代谢产物，不仅是能量代谢中间体，更以“代谢底物”和“信号分子”的双重身份参与肿瘤恶性进程的调控。具体而言，乳酸可通过单羧酸转运体（monocarboxylate transporter，MCT）介导的“乳酸穿梭”实现代谢物跨细胞分配，并借助组蛋白乳酰化修饰调控表观遗传，从而构建能量代谢、氨基酸代谢及脂代谢网络增强肿瘤细胞的代谢可塑性。在免疫调控层面，乳酸诱导T细胞向免疫抑制表型转化，阻碍CD8⁺ T细胞记忆分化并削弱细胞毒性。同时，乳酸不仅能够降低自然杀伤（natural killer，NK）细胞的免疫效能，还通过诱导线粒体功能障碍触发凋亡，为转移灶创造免疫豁免生态位。此外，高水平乳酸激活多条信号转导通路，募集并诱导巨噬细胞向M2型转化，构建免疫逃逸微环境。治疗策略方面，当前研究围绕乳酸代谢的关键环节展开多维度探索。抑制乳酸合成已成为逆转肿瘤代谢优势的重要治疗策略，通过靶向调控乳酸生成和转运的关键分子，减少肿瘤微环境（tumor microenvironment，TME）中乳酸的蓄积，从而削弱其对代谢重编程的驱动作用。此外，促进乳酸分解是当前极具潜力的代谢干预新方向，借助于生物酶或仿生催化系统，新型药物能够增强局部乳酸的清除效率，缓解酸性TME对免疫功能的抑制。本文系统综述乳酸介导的代谢-免疫调控网络，并探讨靶向乳酸通路的精准治疗策略，旨在打破肿瘤细胞的代谢适应性优势与免疫逃逸之间的恶性循环，为探索更高效的抗肿瘤疗法提供系统性的研究方向和转化思路。

关键词: 乳酸, 肿瘤, 乳酸化修饰, 代谢适应性, 肿瘤免疫

Abstract:

Malignant tumors represent a major global public health challenge, necessitating urgent innovation in diagnostic and therapeutic strategies. Lactate, a key metabolic product of tumor cell glycolysis, functions not merely as an energy metabolite but also as a signaling molecule to regulate malignant progression. Lactate mediates intercellular metabolite distribution through monocarboxylate transporter (MCT)-driven lactate shuttling and regulates epigenetics via histone lactylation. This integration establishes interconnected networks of energy, amino acid, and lipid metabolism that enhance tumor metabolic plasticity. In immune regulation, lactate induces a shift of T cells toward immunosuppressive phenotypes, impedes CD8⁺T cell memory differentiation, and attenuates cytotoxicity. Simultaneously, lactate not only reduces the immune efficacy of natural killer (NK) cells but also triggers apoptosis by inducing mitochondrial dysfunction, creating an immune-privileged niche for metastatic sites. Furthermore, elevated lactate levels activate multiple signaling pathways to recruit macrophages and drive their polarization toward the M2 phenotype, fostering an immunosuppressive microenvironment. Current therapeutic strategies target key aspects of lactate metabolism. Inhibiting lactate synthesis reduces lactate accumulation in tumor microenvironment (TME), countering the tumor’s metabolic advantage and diminishing its role in driving metabolic reprogramming. Additionally, promoting the decomposition of lactate represents a promising new direction. Novel agents employing bioenzymes or biomimetic catalytic systems enhance local lactate clearance, alleviating the immunosuppressive effects of the acidic TME. This review comprehensively outlined the lactate-mediated regulatory network, aiming to provide systematic research directions and translational insights for developing more effective anti-tumor therapies.

Key words: Lactate, Tumor, Lactylation modification, Metabolic adaptability, Tumor immunity

中图分类号:

R730.2

王智凌, 陈万金, 程胜桃. 乳酸调控肿瘤恶性进程的研究进展[J]. 中国癌症杂志, 2025, 35(11): 1067-1075.

WANG Zhiling, CHEN Wanjin, CHENG Shengtao. Research progress on the regulation of tumor malignancy by lactate[J]. China Oncology, 2025, 35(11): 1067-1075.

图/表 2

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