{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T05:44:39Z","timestamp":1791870279602,"version":"4.3.4"},"reference-count":153,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T00:00:00Z","timestamp":1791763200000},"content-version":"vor","delay-in-days":11,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Medicine"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Immunotherapy has transformed the treatment landscape for advanced non\u2010small 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\n                      <jats:italic>integrated network<\/jats:italic>\n                      driving immunotherapy resistance and to evaluate emerging therapeutic strategies aimed at overcoming it.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>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\u2010targeted combination therapies and biomarker development was also critically analyzed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The TME orchestrates resistance through highly interconnected axes: (1) cellular circuits including myeloid\u2010derived suppressor cells (MDSCs), regulatory T cells (Tregs), and M2\u2010polarized tumor\u2010associated macrophages (M2\u2010TAMs), (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\u2010excluded architectures. To disrupt this network, rational combination strategies\u2014such as immune checkpoint inhibitors with metabolic modulators (LDHAi), epigenetic drugs, targeted agents (METi), or microbiome interventions\u2014show synergistic potential in early\u2010phase trials. Furthermore, a tiered biomarker system integrating spatial, metabolic, and microbial features is proposed to guide patient stratification.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Overcoming immunotherapy resistance requires a paradigm shift from single\u2010target to network\u2010targeted therapy. This review provides an integrated framework for understanding TME\u2010mediated resistance and translates these insights into a roadmap for clinical translation. Future efforts must prioritize biomarker\u2010validated, rationally designed combination therapies to improve outcomes for patients with resistant NSCLC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cam4.72335","type":"journal-article","created":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T04:49:52Z","timestamp":1791866992000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting the Tumor Microenvironment Network to Overcome Immunotherapy Resistance in Non\u2010Small Cell Lung Cancer: Mechanisms to Clinical Translation"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-2819-4662","authenticated-orcid":false,"given":"Zengrui","family":"Wang","sequence":"first","affiliation":[{"name":"Kunming Medical University  Kunming China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1097-6525","authenticated-orcid":false,"given":"Zhuang","family":"Luo","sequence":"additional","affiliation":[{"name":"Kunming Medical University  Kunming China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-2194-2210","authenticated-orcid":false,"given":"Le","family":"Wang","sequence":"additional","affiliation":[{"name":"Kunming Medical University  Kunming China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiefu","family":"Tang","sequence":"additional","affiliation":[{"name":"Kunming Medical University  Kunming China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Kunming Medical University  Kunming China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinli","family":"Fan","sequence":"additional","affiliation":[{"name":"Kunming Medical University  Kunming China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,12]]},"reference":[{"issue":"3","key":"e_1_2_12_2_1","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung H.","year":"2021","journal-title":"CA: A Cancer Journal for Clinicians"},{"issue":"4","key":"e_1_2_12_3_1","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.cell.2017.01.017","article-title":"Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy","volume":"168","author":"Sharma P.","year":"2017","journal-title":"Cell"},{"issue":"6382","key":"e_1_2_12_4_1","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1126\/science.aar4060","article-title":"Cancer Immunotherapy Using Checkpoint Blockade","volume":"359","author":"Ribas A.","year":"2018","journal-title":"Science"},{"issue":"28","key":"e_1_2_12_5_1","doi-asserted-by":"crossref","first-page":"2518","DOI":"10.1200\/JCO.19.00934","article-title":"Five\u2010Year Overall Survival for Patients With Advanced Non\u2013Small\u2010Cell Lung Cancer Treated With Pembrolizumab: Results From the Phase I KEYNOTE\u2010001 Study","volume":"37","author":"Garon E. 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