{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T11:53:04Z","timestamp":1791373984662,"version":"4.3.1"},"reference-count":236,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"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 (ICIs) targeting the PD-1\/PD-L1 axis have transformed the treatment of Non-Small Cell Lung Cancer (NSCLC), yet durable responses remain limited to a minority of patients. Tumor plasticity is increasingly recognized as a determinant of immunotherapy resistance, although the tumor-intrinsic contribution of immunomodulatory mediators such as IFN-\u03b3 and PD-L1 remains poorly understood. In this review, we examine emerging evidence that IFN-\u03b3 and PD-L1, beyond their established roles in tumor-immune interactions, may contribute to the regulation of NSCLC plasticity. IFN-\u03b3 can activate non-canonical programs involving dose-dependent ICAM1\/PI3K\/AKT\/Notch1 signaling, BCAT1- and FGF2\/\u03b2-catenin-mediated metabolic reprogramming, and a putative autocrine TBX21\/IL-4 signaling circuit that may sustain stem-like properties. PD-L1, in turn, is functionally integrated into plasticity-associated pathways involving the TGF-\u03b2 signaling axis, \u03b2-catenin stabilization, epithelial-to-mesenchymal transition-associated microRNA networks, YAP\/TAZ, CD44 and ATM signaling, as well as TRAF6\/BECN1\/NF-\u03baB-dependent regulation of autophagy. Collectively, these findings support a role for IFN-\u03b3 and PD-L1 as context-dependent modulators of NSCLC plasticity, with potential implications for immunotherapy resistance, and provide a rationale for further exploring combinatorial treatment strategies and patient stratification approaches.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1945729","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T11:16:21Z","timestamp":1791371781000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Beyond immune surveillance: IFN-\u03b3 and PD-L1 as shapers of tumor plasticity in Non-Small Cell Lung Cancer (NSCLC)"],"prefix":"10.3389","volume":"17","author":[{"given":"Stefania","family":"Angelicola","sequence":"first","affiliation":[{"name":"IRCCS Azienda Ospedaliero-Universitaria di Bologna","place":["Bologna, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariateresa","family":"Frascino","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, University of Pavia","place":["Pavia, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilaria C.","family":"Chillico","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, University of Pavia","place":["Pavia, Italy"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick L. 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