{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T22:50:47Z","timestamp":1793659847209,"version":"4.5.1"},"reference-count":35,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T00:00:00Z","timestamp":1750723200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"French national research agency","award":["ANR-23-IAHU-007"],"award-info":[{"award-number":["ANR-23-IAHU-007"]}]},{"name":"French national research agency","award":["ANR-15-IDEX-01"],"award-info":[{"award-number":["ANR-15-IDEX-01"]}]},{"name":"French national research agency","award":["ANR-11-LABX-0028\u201301"],"award-info":[{"award-number":["ANR-11-LABX-0028\u201301"]}]},{"name":"IDEX reference","award":["ANR-23-IAHU-007"],"award-info":[{"award-number":["ANR-23-IAHU-007"]}]},{"name":"IDEX reference","award":["ANR-15-IDEX-01"],"award-info":[{"award-number":["ANR-15-IDEX-01"]}]},{"name":"IDEX reference","award":["ANR-11-LABX-0028\u201301"],"award-info":[{"award-number":["ANR-11-LABX-0028\u201301"]}]},{"name":"\u201cInvestments for the Future\u201d LABEX SIGNALIFE","award":["ANR-23-IAHU-007"],"award-info":[{"award-number":["ANR-23-IAHU-007"]}]},{"name":"\u201cInvestments for the Future\u201d LABEX SIGNALIFE","award":["ANR-15-IDEX-01"],"award-info":[{"award-number":["ANR-15-IDEX-01"]}]},{"name":"\u201cInvestments for the Future\u201d LABEX SIGNALIFE","award":["ANR-11-LABX-0028\u201301"],"award-info":[{"award-number":["ANR-11-LABX-0028\u201301"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Programmed Death-Ligand 1 (PD-L1) is a major target for immunotherapy using checkpoint inhibitors (CPIs), particularly in lung cancer treatment. Tumoral PD-L1 expression has been recognized as a natural predictor of CPI response. This predictive relationship is primarily due to its upregulation by interferon-gamma, which is released by immune cells (mainly T lymphocytes and natural killer cells) in proximity to tumor cells, driving an immune resistance mechanism. However, PD-L1 expression is modulated at multiple levels, including oncogenic signaling pathways, and transcriptional and post-transcriptional regulations, potentially leading to false positive predictions. Conversely, variable glycosylation of PD-L1 may compromise the accuracy of immunohistochemical measurements, resulting in false negative predictive data. In addition, PD-L1 expression demonstrates relative instability throughout treatment courses (e.g., chemotherapy and tyrosine kinase inhibitors), further limiting its clinical utility. In this review, we focused on the molecular mechanisms governing PD-L1 expression with a special emphasis on lung cancer. We also discussed biomarker strategies for optimizing patient selection for checkpoint inhibitor therapy where multimodal\/multi-omics meta-biomarker approaches are emerging. Such comprehensive PD-L1-enriched biomarker strategies require evaluation through large-scale prospective studies, particularly in lung cancer, where numerous competing predictive candidates exist for CPI response.<\/jats:p>","DOI":"10.3390\/ijms26136066","type":"journal-article","created":{"date-parts":[[2025,6,24]],"date-time":"2025-06-24T09:24:18Z","timestamp":1750757058000},"page":"6066","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["PD-L1 Expression in NSCLC: Clouds in a Bright Sky"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4403-1808","authenticated-orcid":false,"given":"Victoria","family":"Ferrari","sequence":"first","affiliation":[{"name":"Antoine Lacassagne Center, Department of Medical Oncology, University C\u00f4te d\u2019Azur, 33 Avenue de Valombrose, 06189 Nice, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1802-118X","authenticated-orcid":false,"given":"Jocelyn","family":"Gal","sequence":"additional","affiliation":[{"name":"Antoine Lacassagne Center, Department of Epidemiology and Biostatistics, University C\u00f4te d\u2019Azur, 33 Avenue de Valombrose, 06189 Nice, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1025-3429","authenticated-orcid":false,"given":"Baharia","family":"Mograbi","sequence":"additional","affiliation":[{"name":"FHU OncoAge, IHU RespirERA, IRCAN, Inserm, CNRS 7284, U1081, University C\u00f4te d\u2019Azur, 06189 Nice, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerard","family":"Milano","sequence":"additional","affiliation":[{"name":"Antoine Lacassagne Center, University C\u00f4te d\u2019Azur, 33 Avenue de Valombrose, 06189 Nice, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1146\/annurev.immunol.26.021607.090331","article-title":"PD-1 and its ligands in tolerance and immunity","volume":"26","author":"Keir","year":"2008","journal-title":"Annu. 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