{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T09:18:37Z","timestamp":1787822317408,"version":"build-2784847793"},"reference-count":23,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T00:00:00Z","timestamp":1787788800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Turkish Society of Medical Oncology"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Clin. Med.","JCM"],"abstract":"<jats:p>Background: Lung cancer remains the leading cause of cancer-related mortality, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases. Over the past decade, immune checkpoint inhibitors have become a core component of first-line treatment for advanced-stage NSCLC lacking driver mutations. Programmed death-ligand 1 (PD-L1) expression is currently used as the standard biomarker, yet its predictive value remains limited, and in most immunotherapy trials, treatment efficacy has been observed independently of PD-L1 expression status. Enhancer of zeste homolog 2 (EZH2), an epigenetic regulator, promotes immune escape by suppressing antigen presentation and impairing CD8+ T-cell function, thereby generating an immune-cold tumor microenvironment, positioning it as a promising candidate biomarker. Methods: We retrospectively analyzed 102 NSCLC patients treated with immunotherapy at a single center between 2018 and 2024. EZH2 expression was assessed by immunohistochemistry. A cohort-derived 25% threshold was used for the primary exploratory analysis, and the analyses were repeated using a 50% threshold as a sensitivity analysis. Patients were classified as EZH2-high (45.1%) and EZH2-low (54.9%) at the 25% threshold. Results: At the 25% threshold, objective response rate (ORR) was 53.6% in the EZH2-low group and 45.7% in the EZH2-high group (Fisher\u2019s exact p = 0.551), while disease control rate (DCR) was 64.3% and 60.9%, respectively (p = 0.837). Median overall survival (OS) was 37 versus 27 months (log-rank p = 0.323), and median progression-free survival (PFS) was 15 versus 12 months (p = 0.387). No significant correlation was found between EZH2 and PD-L1 expression (r = 0.167, p = 0.138). In treatment-line-adjusted Cox models, EZH2 expression was not associated with OS (hazard ratio (HR) 0.953, 95% confidence interval (CI) 0.533\u20131.704; p = 0.870) or PFS (HR 0.996, 95% CI 0.573\u20131.733; p = 0.989), whereas squamous histology was an independent predictor of survival. Results remained non-significant at the 50% threshold. Early progression was uncommon and did not differ significantly by EZH2 status overall or within PD-L1 strata. Conclusions: In this real-world cohort, EZH2 expression was not independently associated with response, early progression, OS, or PFS, and showed no correlation with PD-L1. These exploratory findings do not support the clinical use of EZH2 as a biomarker at this stage; prospective, multicenter studies using predefined thresholds and standardized immunohistochemical methods are needed to clarify its potential role as a marker complementary to PD-L1.<\/jats:p>","DOI":"10.3390\/jcm15176611","type":"journal-article","created":{"date-parts":[[2026,8,27]],"date-time":"2026-08-27T08:02:27Z","timestamp":1787817747000},"page":"6611","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["EZH2 Expression and Clinical Outcomes in Non-Small Cell Lung Cancer Patients Treated with Immune Checkpoint Inhibitors: A Real-World Retrospective Cohort Study"],"prefix":"10.3390","volume":"15","author":[{"given":"Esra","family":"Asarkaya","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Cukurova University Faculty of Medicine, 01330 Adana, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-1366-5552","authenticated-orcid":false,"given":"Hatice","family":"Asoglu","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Cukurova University Faculty of Medicine, 01330 Adana, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2671-9393","authenticated-orcid":false,"given":"Abdurrahman","family":"Aykut","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Cukurova University Faculty of Medicine, 01330 Adana, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8914-7911","authenticated-orcid":false,"given":"Gunes Dorukhan","family":"Cavusoglu","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Cukurova University Faculty of Medicine, 01330 Adana, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2435-368X","authenticated-orcid":false,"given":"Yasemin","family":"Ayd\u0131nalp","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Sanl\u0131urfa Mehmet Akif \u0130nan Training and Research Hospital, 63300 \u015eanl\u0131urfa, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5264-8405","authenticated-orcid":false,"given":"Sendag","family":"Yasl\u0131kaya","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Giresun Training and Research Hospital, 28100 Giresun, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1377-0488","authenticated-orcid":false,"given":"Suheda","family":"Atas Ipek","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Cukurova University Faculty of Medicine, 01330 Adana, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatma","family":"Calkan","sequence":"additional","affiliation":[{"name":"Department of Pathology, Cukurova University Faculty of Medicine, 01330 Adana, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1447-1060","authenticated-orcid":false,"given":"Emine","family":"Kilic Bagir","sequence":"additional","affiliation":[{"name":"Department of Pathology, Cukurova University Faculty of Medicine, 01330 Adana, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7129-3424","authenticated-orcid":false,"given":"Derya","family":"Gumurdulu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Cukurova University Faculty of Medicine, 01330 Adana, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hulya","family":"Binokay","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, Cukurova University Faculty of Medicine, 01330 Adana, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tolga","family":"Koseci","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Cukurova University Faculty of Medicine, 01330 Adana, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ismail Oguz","family":"Kara","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Cukurova University Faculty of Medicine, 01330 Adana, T\u00fcrkiye"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Berksoy","family":"Sahin","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Cukurova University Faculty of Medicine, 01330 Adana, 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