{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T12:20:58Z","timestamp":1788524458281,"version":"build-2803163510"},"reference-count":88,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T00:00:00Z","timestamp":1788480000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Immune checkpoint inhibitors have improved outcomes in small-cell lung cancer (SCLC), yet durable benefit remains limited, and the immune consequences of SCLC transformation from EGFR-mutant lung adenocarcinoma (LUAD) remain incompletely understood. Conventional explanations for resistance emphasize PD-L1 expression, tumor mutational burden, T-cell dysfunction, myeloid suppression, and stromal exclusion, but these factors do not fully explain how lineage-state changes alter tumor recognition. Here, we examine lineage plasticity as a potential tumor-cell-intrinsic contributor to immune resistance. We use the term \u201cimmune invisibility\u201d narrowly to denote failure of tumor-cell recognition caused primarily by impaired MHC-I antigen processing and presentation. This state is distinguished from immune exclusion and T-cell dysfunction, although the three barriers may coexist. Evidence linking neuroendocrine state to reduced antigen presentation is strongest in primary SCLC and experimental SCLC models. In EGFR-mutant lung adenocarcinoma undergoing SCLC transformation, analogous changes remain biologically plausible but have not been established in paired longitudinal specimens. Therapeutically, checkpoint blockade alone may be insufficient when tumor recognition or T-cell entry is impaired. Clinically established approaches include chemoimmunotherapy in defined SCLC settings and DLL3-directed T-cell engagement in previously treated disease, whereas epigenetic combinations, STING\/IFN activation, most antibody-drug conjugates, and cellular therapies remain investigational. Integrating lineage state, antigen-presentation capacity, immune localization, and retained surface targets may provide a framework for distinguishing immune-restoration from immune-redirection strategies.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1900927","type":"journal-article","created":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T12:01:24Z","timestamp":1788523284000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Lineage plasticity and immune invisibility in primary SCLC and LUAD-to-SCLC transformation: antigen presentation loss and therapeutic redirection"],"prefix":"10.3389","volume":"17","author":[{"given":"Hongying","family":"Xu","sequence":"first","affiliation":[{"name":"Department of Oncology, The First Affiliated Hospital of Chongqing Medical and Pharmaceutical College","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benhua","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, The Second People\u2019s Hospital of Liangshan Yi Autonomous Prefecture","place":["Xichang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, The Second People\u2019s Hospital of Liangshan Yi Autonomous Prefecture","place":["Xichang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Care Medicine, People\u2019s Hospital of Chongqing Liangjiang New Area","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1606774","article-title":"Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer","volume":"375","author":"Reck","year":"2016","journal-title":"N Engl J Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1801005","article-title":"Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer","volume":"378","author":"Gandhi","year":"2018","journal-title":"N Engl J Med"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1810865","article-title":"Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer","volume":"379","author":"Paz-Ares","year":"2018","journal-title":"N Engl J Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1910231","article-title":"Nivolumab plus ipilimumab in advanced non-small-cell lung cancer","volume":"381","author":"Hellmann","year":"2019","journal-title":"N Engl J Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1709937","article-title":"Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer","volume":"377","author":"Antonia","year":"2017","journal-title":"N Engl J Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa1809064","article-title":"First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer","volume":"379","author":"Horn","year":"2018","journal-title":"N Engl J Med"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(19)32222-6","article-title":"Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial","volume":"394","author":"Paz-Ares","year":"2019","journal-title":"Lancet"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1056\/nejmoa2404873","article-title":"Durvalumab after chemoradiotherapy in limited-stage small-cell lung cancer","volume":"391","author":"Cheng","year":"2024","journal-title":"N Engl J Med"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.ccr-15-3101","article-title":"EGFR mutations and ALK rearrangements are associated with low response rates to PD-1 pathway blockade in non-small cell lung cancer: a retrospective analysis","volume":"22","author":"Gainor","year":"2016","journal-title":"Clin Cancer Res Off J Am Assoc For Cancer Res"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa1348","article-title":"Cancer immunology. 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