通讯作者: 于戈, whyuge@126.com

DOI：10.12201/bmr.202603.00010

Targeting Tumor Microenvironment Metabolic Reprogramming: A New Strategy to Overcome Treatment Resistance in NSCLCZHI Chuanrui1,TANG Jian2,YU Ge2*

• 摘要：尽管靶向治疗与免疫治疗已成为非小细胞肺癌（non-small cell lung cancer，NSCLC）的关键治疗手段，显著改善了患者预后，但获得性耐药仍是限制长期获益的核心瓶颈，而肿瘤微环境（tumor microenvironment，TME）的代谢重编程是驱动耐药的关键枢纽。本研究系统阐释了介导NSCLC治疗耐受的多元协同机制，重点解析了癌相关成纤维细胞（cancer-associated fibroblasts，CAFs）介导的代谢共生、乳酸积聚引发的酸性屏蔽与表观遗传重构、缺氧诱导的代谢适应与干细胞特性维持，以及关键基因突变如肝激酶B1（liver kinase B1，LKB1）/Kelch 样环氧氯丙烷相关蛋白 1（Kelch-like ECH-associated protein 1，KEAP1）驱动的代谢-免疫偶联失调。上述机制通过协同交互实现代谢重编程与免疫抑制的深度偶联：CAFs分泌的乳酸既是酸性微环境的物质基础，又通过表观修饰驱动免疫细胞向免疫抑制表型极化；缺氧应激不仅诱导肿瘤细胞代谢重塑，还通过外泌体等途径调控免疫微环境；而LKB1/KEAP1突变背景下的营养竞争，则进一步导致效应免疫细胞代谢功能障碍。基于这一整合视角，本研究探讨了靶向关键代谢节点的联合治疗策略，旨在突破单靶点干预局限，为逆转NSCLC耐药提供理论依据。

  关键词： 非小细胞肺癌；肿瘤微环境；代谢重编程；治疗耐受

   

  Abstract: Despite targeted therapy and immunotherapy have revolutionized the clinical management of non-small cell lung cancer (NSCLC), inevitable acquired resistance remains the core clinical bottleneck restricting long-term patient survival. Metabolic reprogramming within the tumor microenvironment (TME) has been widely recognized as a critical hub driving the evolution of such therapeutic resistance. This review systematically elaborates the diverse and synergistic mechanisms mediating NSCLC therapeutic resistance, with a focus on cancer-associated fibroblasts (CAFs)-orchestrated metabolic symbiosis, lactic acid accumulation-induced acidic shielding and epigenetic remodeling, hypoxia-triggered metabolic adaptation and stemness maintenance, as well as metabolic-immune uncoupling driven by key gene mutations (e.g., LKB1/KEAP1). The novelty of this review lies in the proposal of an integrated framework termed the metabolically-immunosuppressive tumor microenvironment (M-ITME), which unifies discrete metabolic events into a systemic network underlying therapeutic resistance. On this basis, we further discuss combinatorial therapeutic strategies targeting metabolic checkpoints, aiming to break through the limitations of single-target interventions. This review not only provides a novel perspective for in-depth deciphering the networked logic between TME metabolic heterogeneity and therapeutic resistance, but also offers a theoretically sound and highly translationally relevant foundation and roadmap for designing individualized combinatorial regimens to reverse NSCLC resistance.

  Key words:

  提交时间：2026-03-06

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• 序号	提交日期	编号	操作
  1	2026-02-14	10.12201/bmr.202603.00010V1	下载

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