{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T21:06:43Z","timestamp":1789592803960,"version":"build-2803163510"},"reference-count":106,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T00:00:00Z","timestamp":1758499200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Over the last decade, immunotherapy has revolutionized lung cancer treatments, particularly in non-small cell lung cancer, where immune checkpoint inhibitors have achieved significant clinical success. However, high percentages of patients do not respond initially or eventually develop a resistance to these therapies. This review explores the evolution and challenges of immunotherapy in lung cancer, highlighting its clinical milestones and intrinsic and extrinsic resistance mechanisms. We investigate tumor-intrinsic resistance factors, including alterations in antigen presentation, the loss of Beta-2 microglobulin function, impaired interferon signaling, immune editing, epigenetic modifications, and tumor-extrinsic resistance, such as an immunosuppressive lung tumor microenvironment, dysregulated cytokine profiles, and the upregulation of immune checkpoints. Then, we focus on the emerging role of resistance biomarkers and the development of personalized treatment strategies to overcome these challenges. The complex interplay between tumor biology and immune modulation in lung cancer paves the way for novel approaches for improving the effectiveness of immunotherapeutic treatments.<\/jats:p>","DOI":"10.3390\/ijms26189244","type":"journal-article","created":{"date-parts":[[2025,9,22]],"date-time":"2025-09-22T13:04:44Z","timestamp":1758546284000},"page":"9244","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Unraveling Resistance in Lung Cancer Immunotherapy: Clinical Milestones, Mechanistic Insights, and Future Strategies"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4399-3132","authenticated-orcid":false,"given":"Maria","family":"Vitale","sequence":"first","affiliation":[{"name":"CEINGE-Biotecnologie Avanzate Franco Salvatore, 80145 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2902-3558","authenticated-orcid":false,"given":"Raffaella","family":"Pagliaro","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Sciences, University of Campania L. Vanvitelli, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4473-9387","authenticated-orcid":false,"given":"Giuseppe","family":"Viscardi","sequence":"additional","affiliation":[{"name":"Department of Pneumology and Oncology, Monaldi Hospital, AORN dei Colli, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6894-9317","authenticated-orcid":false,"given":"Lucio","family":"Pastore","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Castaldo","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Perrotta","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Sciences, University of Campania L. Vanvitelli, 80131 Naples, Italy"},{"name":"U.O.C. Clinica Pneumologica L. Vanvitelli, Monaldi Hospital, AORN dei Colli, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3667-9902","authenticated-orcid":false,"given":"Susan F.","family":"Campbell","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Sciences, University of Campania L. Vanvitelli, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4692-5901","authenticated-orcid":false,"given":"Andrea","family":"Bianco","sequence":"additional","affiliation":[{"name":"Department of Translational Medical Sciences, University of Campania L. Vanvitelli, 80131 Naples, Italy"},{"name":"U.O.C. Clinica Pneumologica L. Vanvitelli, Monaldi Hospital, AORN dei Colli, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1121-7315","authenticated-orcid":false,"given":"Filippo","family":"Scial\u00f2","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,22]]},"reference":[{"key":"ref_1","first-page":"158","article-title":"Oncolytic adenovirus treatment induces the reduction of tumor dimension in a model of mice lung adenocarcinoma multicellular spheroids","volume":"47","author":"Vitale","year":"2023","journal-title":"Biochim. 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