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Exploration of the tumor microenvironment (TME) has resulted in dramatic advancements in the treatment of NSCLC through the advent of immunotherapy. Indeed, anti-programmed death (PD) ligand 1\/PD-1 checkpoint inhibitor therapy has substantially improved survival for advanced, unresectable disease and is now being increasingly utilized in the perioperative setting for early-stage, resectable tumors. This success has generated vigorous interest in exploring other cellular players in the NSCLC TME that could be potentially targeted for therapeutic benefit. In this review, we discuss the current state of therapeutic targets in the NSCLC TME, reflect on the revolution of immunotherapy and future directions for its utilization, and reflect on how the current investigations into TME-specific targets may impact thoracic surgical care.<\/jats:p>","DOI":"10.3390\/cancers17111732","type":"journal-article","created":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T04:32:37Z","timestamp":1747888357000},"page":"1732","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["The Current State of Tumor Microenvironment-Specific Therapies for Non-Small Cell Lung Cancer"],"prefix":"10.3390","volume":"17","author":[{"given":"Raghav","family":"Chandra","sequence":"first","affiliation":[{"name":"Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasmina","family":"Ehab","sequence":"additional","affiliation":[{"name":"Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Hauptmann","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naga Swati","family":"Gunturu","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7601-5776","authenticated-orcid":false,"given":"John D.","family":"Karalis","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2464-2747","authenticated-orcid":false,"given":"Daniel O.","family":"Kent","sequence":"additional","affiliation":[{"name":"Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher A.","family":"Heid","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott I.","family":"Reznik","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inderpal S.","family":"Sarkaria","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular and Thoracic Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huocong","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"},{"name":"Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2704-2377","authenticated-orcid":false,"given":"Rolf A.","family":"Brekken","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"},{"name":"Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7776-0767","authenticated-orcid":false,"given":"John D.","family":"Minna","sequence":"additional","affiliation":[{"name":"Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"},{"name":"Department of Internal Medicine and Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"229","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA A Cancer J. 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