{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T18:50:41Z","timestamp":1791399041091,"version":"4.3.3"},"reference-count":77,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T00:00:00Z","timestamp":1769126400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,6,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy with dismal prognosis. Although immune checkpoint inhibitors (ICIs) have revolutionized non-small cell lung cancer, their impact in SCLC has been modest, with only 2\u20133\u2009months\u2019 improvement in median survival. This paradox persists despite SCLC\u2019s high tumor mutational burden, suggesting complex, multifactorial resistance mechanisms. Here we critically review the latest advances in understanding immunotherapy resistance in SCLC. We highlight tumor-intrinsic immune escape mechanisms, including genetic drivers, MHC class I downregulation, and epigenetic repression, as well as the profoundly immunosuppressive tumor microenvironment. We also examine the evolving classification of SCLC into molecular subtypes, which reveals distinct immunogenic landscapes with potential predictive value for immunotherapy response. Importantly, we integrate a comprehensive update on ongoing and recently reported clinical trials that aim to restore immune responsiveness, ranging from combination ICI regimens to novel strategies involving epigenetic modulators, antigen presenting pathway agonists, and bispecific T-cell engagers. Finally, we discuss translational strategies to overcome immunotherapy resistance and outline a precision immunotherapy roadmap, arguing for biomarker-guided and subtype-stratified clinical trial design. By synthesizing mechanistic, translational, and clinical perspectives, this review provides a framework for rational therapeutic innovation in SCLC.<\/jats:p>","DOI":"10.1093\/ajrccm\/aamaf124","type":"journal-article","created":{"date-parts":[[2026,1,5]],"date-time":"2026-01-05T12:22:14Z","timestamp":1767615734000},"page":"1100-1114","source":"Crossref","is-referenced-by-count":4,"title":["Cracking the code of immunotherapy resistance in small cell lung cancer: molecular insights and emerging solutions"],"prefix":"10.1093","volume":"212","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9620-745X","authenticated-orcid":false,"given":"Kostas A","family":"Papavassiliou","sequence":"first","affiliation":[{"name":"First University Department of Respiratory Medicine, \u201cSotiria\u201d Chest Hospital, Medical School, National and Kapodistrian University of Athens , Athens,","place":["Greece"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9535-2134","authenticated-orcid":false,"given":"Dimitrios J","family":"Stravopodis","sequence":"additional","affiliation":[{"name":"Section of Cell Biology and Biophysics, Department of Biology, School of Science, National and Kapodistrian University of Athens , Athens,","place":["Greece"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-3904-1442","authenticated-orcid":false,"given":"Vassiliki A","family":"Gogou","sequence":"additional","affiliation":[{"name":"First University Department of Respiratory Medicine, \u201cSotiria\u201d Chest Hospital, Medical School, National and Kapodistrian University of Athens , Athens,","place":["Greece"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5803-4527","authenticated-orcid":false,"given":"Athanasios G","family":"Papavassiliou","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens , Athens,","place":["Greece"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,1,23]]},"reference":[{"key":"2026061022143746100_aamaf124-B1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21708","article-title":"Cancer statistics, 2022","volume":"72","author":"Siegel","year":"2022","journal-title":"CA Cancer J Clin"},{"key":"2026061022143746100_aamaf124-B2","doi-asserted-by":"publisher","first-page":"620","DOI":"10.3322\/caac.21785","article-title":"Clinical insights into small cell lung cancer: tumor heterogeneity, diagnosis, therapy, and future directions","volume":"73","author":"Megyesfalvi","year":"2023","journal-title":"CA Cancer J 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