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Review Open Access

Tumor microenvironment‑mediated resistance to immune checkpoint inhibitors in non‑small cell lung cancer: Mechanisms, combination strategies and clinical perspectives (Review)

  • Authors:
    • Jiange Mu
    • Qiqi Xu
  • View Affiliations / Copyright

    Affiliations: School of Clinical Medicine, Changchun University of Chinese Medicine, Changchun, Jilin 130000, P.R. China, Department of Thoracic Surgery, Beijing Jishuitan Hospital Affiliated to Capital Medical University, Beijing 100000, P.R. China
    Copyright: © Mu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 62
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    Published online on: August 13, 2026
       https://doi.org/10.3892/mco.2026.2971
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Abstract

Non‑small cell lung cancer (NSCLC) is one of the leading causes of cancer‑associated mortality worldwide. Immune checkpoint inhibitors targeting programmed cell death protein 1, programmed death‑ligand 1 (PD‑L1) and cytotoxic T lymphocyte‑associated protein 4 have transformed the treatment landscape of NSCLC. However, primary and acquired resistance limit durable clinical benefit. The current review article aimed to summarize tumor microenvironment‑mediated resistance as an interconnected biological process rather than a collection of isolated factors. Immunosuppressive myeloid populations, regulatory lymphocytes, cancer‑associated fibroblasts, extracellular matrix remodeling, vascular endothelial growth factor‑driven vascular dysfunction, hypoxia, transforming growth factor‑β signaling and metabolic reprogramming cooperate with defects in antigen presentation, dysregulation of serine/threonine kinase 11/Kelch‑like ECH‑associated protein 1/nuclear factor erythroid 2‑related factor 2/stimulator of interferon genes and oncogenic driver signaling to generate immune‑desert (minimal immune cell infiltration), immune‑excluded (immune cells retained outside tumors) or exhausted immune‑inflamed (immune‑cell infiltration with functional exhaustion) phenotypes. The present review also critically evaluated combination therapeutic strategies, distinguishing phase III‑supported standards from early‑phase clinical or preclinical approaches, while highlighting considerations associated with patient selection, toxicity and the evolving regulatory context. Finally, an operational biomarker framework integrating PD‑L1 expression, tumor mutational burden, interferon γ‑associated signatures, spatial profiling, circulating tumor DNA, exosomal biomarkers and microbiome features was proposed to guide precision immunotherapy in NSCLC.
View Figures

Figure 1

Integrated model of tumor
microenvironment-mediated resistance to ICIs in non-small cell lung
cancer, including immune-desert, immune-excluded and exhausted
immune-inflamed phenotypes. An immune-desert, or cold, tumor has
minimal immune-cell infiltration. B2M, β2 microglobulin; HLA-I,
human leukocyte antigen class I; STK11, serine/threonine kinase 11;
TAM, tumor-associated macrophage; M-MDSC, monocytic myeloid-derived
suppressor cell; PMN-MDSC, polymorphonuclear myeloid-derived
suppressor cell; Treg, regulatory T cell; CAF, cancer-associated
fibroblast; ECM, extracellular matrix; ICI, immune checkpoint
inhibitor.

Figure 2

Evidence-stratified tumor
microenvironment-oriented therapeutic strategies. ICI, immune
checkpoint inhibitor; NSCLC, non-small cell lung cancer; chemo,
chemotherapy; PACIFIC, phase III trial of durvalumab after
concurrent chemoradiotherapy in unresectable stage III NSCLC; CRT,
chemoradiotherapy; TMB, tumor mutational burden; ctDNA, circulating
tumor DNA; TKI, tyrosine kinase inhibitor; TIGIT, T cell
immunoreceptor with Ig and ITIM domains; LAG-3, lymphocyte
activation gene 3; TIM-3, T cell immunoglobulin and mucin-domain
containing protein 3.
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Copy and paste a formatted citation
Spandidos Publications style
Mu J and Xu Q: Tumor microenvironment‑mediated resistance to immune checkpoint inhibitors in non‑small cell lung cancer: Mechanisms, combination strategies and clinical perspectives (Review). Mol Clin Oncol 25: 62, 2026.
APA
Mu, J., & Xu, Q. (2026). Tumor microenvironment‑mediated resistance to immune checkpoint inhibitors in non‑small cell lung cancer: Mechanisms, combination strategies and clinical perspectives (Review). Molecular and Clinical Oncology, 25, 62. https://doi.org/10.3892/mco.2026.2971
MLA
Mu, J., Xu, Q."Tumor microenvironment‑mediated resistance to immune checkpoint inhibitors in non‑small cell lung cancer: Mechanisms, combination strategies and clinical perspectives (Review)". Molecular and Clinical Oncology 25.4 (2026): 62.
Chicago
Mu, J., Xu, Q."Tumor microenvironment‑mediated resistance to immune checkpoint inhibitors in non‑small cell lung cancer: Mechanisms, combination strategies and clinical perspectives (Review)". Molecular and Clinical Oncology 25, no. 4 (2026): 62. https://doi.org/10.3892/mco.2026.2971
Copy and paste a formatted citation
x
Spandidos Publications style
Mu J and Xu Q: Tumor microenvironment‑mediated resistance to immune checkpoint inhibitors in non‑small cell lung cancer: Mechanisms, combination strategies and clinical perspectives (Review). Mol Clin Oncol 25: 62, 2026.
APA
Mu, J., & Xu, Q. (2026). Tumor microenvironment‑mediated resistance to immune checkpoint inhibitors in non‑small cell lung cancer: Mechanisms, combination strategies and clinical perspectives (Review). Molecular and Clinical Oncology, 25, 62. https://doi.org/10.3892/mco.2026.2971
MLA
Mu, J., Xu, Q."Tumor microenvironment‑mediated resistance to immune checkpoint inhibitors in non‑small cell lung cancer: Mechanisms, combination strategies and clinical perspectives (Review)". Molecular and Clinical Oncology 25.4 (2026): 62.
Chicago
Mu, J., Xu, Q."Tumor microenvironment‑mediated resistance to immune checkpoint inhibitors in non‑small cell lung cancer: Mechanisms, combination strategies and clinical perspectives (Review)". Molecular and Clinical Oncology 25, no. 4 (2026): 62. https://doi.org/10.3892/mco.2026.2971
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