Cancer medicine · 2026
Targeting the Tumor Microenvironment Network to Overcome Immunotherapy Resistance in Non-Small Cell Lung Cancer: Mechanisms to Clinical Translation.
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Wang Zengrui, Luo Zhuang, Wang Le, Tang Jiefu, Zhang Zhi, Fan Xinli
Аннотация
BACKGROUND: Immunotherapy has transformed the treatment landscape for advanced non-small cell lung cancer (NSCLC), yet resistance mediated by the tumor microenvironment (TME) limits its efficacy in most patients. This review aims to synthesize the current understanding of the TME as an integrated network driving immunotherapy resistance and to evaluate emerging therapeutic strategies aimed at overcoming it.
METHODS: We conducted a comprehensive narrative review of key literature in the field, sourced from PubMed and major conference proceedings. The focus was on mechanistic studies elucidating immunosuppressive cell circuits, metabolic reprogramming, epigenetic regulation, spatial heterogeneity, and microbiome interactions within the lung cancer TME. Preclinical and clinical evidence for TME-targeted combination therapies and biomarker development was also critically analyzed.
RESULTS: The TME orchestrates resistance through highly interconnected axes: (1) cellular circuits including myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and M2-polarized tumor-associated macrophages (M2-TAMs), (2) metabolic barriers (lactate acidosis, nutrient depletion), (3) epigenetic reprogramming, and (4) systemic communication via exosomes and the microbiome. Spatial transcriptomics reveals that driver mutations (e.g., EGFR, KRAS) shape distinct immune-excluded architectures. To disrupt this network, rational combination strategies-such as immune checkpoint inhibitors with metabolic modulators (LDHAi), epigenetic drugs, targeted agents (METi), or microbiome interventions-show synergistic potential in early-phase trials. Furthermore, a tiered biomarker system integrating spatial, metabolic, and microbial features is proposed to guide patient stratification.
CONCLUSION: Overcoming immunotherapy resistance requires a paradigm shift from single-target to network-targeted therapy. This review provides an integrated framework for understanding TME-mediated resistance and translates these insights into a roadmap for clinical translation. Future efforts must prioritize biomarker-validated, rationally designed combination therapies to improve outcomes for patients with resistant NSCLC.
METHODS: We conducted a comprehensive narrative review of key literature in the field, sourced from PubMed and major conference proceedings. The focus was on mechanistic studies elucidating immunosuppressive cell circuits, metabolic reprogramming, epigenetic regulation, spatial heterogeneity, and microbiome interactions within the lung cancer TME. Preclinical and clinical evidence for TME-targeted combination therapies and biomarker development was also critically analyzed.
RESULTS: The TME orchestrates resistance through highly interconnected axes: (1) cellular circuits including myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and M2-polarized tumor-associated macrophages (M2-TAMs), (2) metabolic barriers (lactate acidosis, nutrient depletion), (3) epigenetic reprogramming, and (4) systemic communication via exosomes and the microbiome. Spatial transcriptomics reveals that driver mutations (e.g., EGFR, KRAS) shape distinct immune-excluded architectures. To disrupt this network, rational combination strategies-such as immune checkpoint inhibitors with metabolic modulators (LDHAi), epigenetic drugs, targeted agents (METi), or microbiome interventions-show synergistic potential in early-phase trials. Furthermore, a tiered biomarker system integrating spatial, metabolic, and microbial features is proposed to guide patient stratification.
CONCLUSION: Overcoming immunotherapy resistance requires a paradigm shift from single-target to network-targeted therapy. This review provides an integrated framework for understanding TME-mediated resistance and translates these insights into a roadmap for clinical translation. Future efforts must prioritize biomarker-validated, rationally designed combination therapies to improve outcomes for patients with resistant NSCLC.