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

Corresponding author: Yu Ge, whyuge@126.com

DOI: 10.12201/bmr.202603.00010

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  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:

  Submit time: 6 March 2026

  Copyright: The copyright holder for this preprint is the author/funder, who has granted biomedRxiv a license to display the preprint in perpetuity.
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