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However, the prognostic value of coordinated cytokine-related transcriptional programs across cancer types has not been systematically explored. Pan-cancer transcriptomic and clinical data were analyzed to construct a cytokine-related prognostic signature using least absolute shrinkage and selection operator (LASSO) Cox regression. Patients were stratified into high-risk and low-risk groups based on the derived risk score. Prognostic performance was evaluated in training and test cohorts, and biological relevance was assessed through survival analyses and pathway-level investigations. A 16-gene cytokine-related signature was established that consistently stratified patients into distinct prognostic groups across multiple cancer types. High cytokine-related risk scores were significantly associated with unfavorable survival outcomes and were linked to enhanced cell cycle activity, epithelial-mesenchymal transition, and extracellular matrix remodeling. Integration of the risk score with clinical variables improved individualized survival prediction. Immunohistochemical analyses further confirmed increased protein expression of representative risk-associated genes, including pannexin 1 (PANX1) and FERM domain containing 8 (FRMD8), in multiple tumor tissues compared with corresponding normal tissues. The cytokine-related prognostic signature captures key inflammatory and immune-related programs underlying tumor aggressiveness and provides a robust tool for pan-cancer risk stratification with potential clinical utility.<\/jats:p>","DOI":"10.3390\/ijms27062830","type":"journal-article","created":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T09:48:42Z","timestamp":1774259322000},"page":"2830","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Cytokine-Related Gene Signature for Pan-Cancer Prognostic Stratification and Malignant Phenotype Characterization"],"prefix":"10.3390","volume":"27","author":[{"given":"Shih-Chieh","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Kaohsiung Armed Forces General Hospital, National Defense Medical University, Kaohsiung 80284, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kai-Fu","family":"Chang","sequence":"additional","affiliation":[{"name":"Medical Laboratory, Medical Education and Research Center, Kaohsiung Armed Forces General Hospital, National Defense Medical University, Kaohsiung 80284, Taiwan"},{"name":"Division of Experimental Surgery Center, Department of Surgery, Tri-Service General Hospital, National Defense Medical University, Taipei 11490, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chien-Cheng","family":"Chao","sequence":"additional","affiliation":[{"name":"Medical Laboratory, Medical Education and Research Center, Kaohsiung Armed Forces General Hospital, National Defense Medical University, Kaohsiung 80284, Taiwan"},{"name":"Division of Experimental Surgery Center, Department of Surgery, Tri-Service General Hospital, National Defense Medical University, Taipei 11490, 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Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan"},{"name":"Yogananda School of AI Computers and Data Sciences, Shoolini University, Solan 173229, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Do Thi Minh","family":"Xuan","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy, Van Lang University, 69\/68 Dang Thuy Tram Street, Binh Loi Trung Ward, Ho Chi Minh City 70000, Vietnam"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-1269-2397","authenticated-orcid":false,"given":"Neethu","family":"Palekkode","sequence":"additional","affiliation":[{"name":"PhD Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei 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