{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T14:45:10Z","timestamp":1785422710448,"version":"3.56.0"},"reference-count":50,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,25]],"date-time":"2026-04-25T00:00:00Z","timestamp":1777075200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004731","name":"Zhejiang Provincial Natural Science Foundation","doi-asserted-by":"publisher","award":["LZ22H160008"],"award-info":[{"award-number":["LZ22H160008"]}],"id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004731","name":"Zhejiang Provincial Natural Science Foundation","doi-asserted-by":"publisher","award":["LTGY24H160020"],"award-info":[{"award-number":["LTGY24H160020"]}],"id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]},{"award":["LZ22H160008"],"award-info":[{"award-number":["LZ22H160008"]}],"id":[{"id":"https:\/\/ror.org\/04aqat463","id-type":"ROR","asserted-by":"publisher"}]},{"award":["LTGY24H160020"],"award-info":[{"award-number":["LTGY24H160020"]}],"id":[{"id":"https:\/\/ror.org\/04aqat463","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Clear cell renal cell carcinoma (ccRCC) involves complex interactions between immune evasion and metabolic reprogramming. This study aimed to characterize ccRCC through integrated immunometabolic profiling, develop a prognostic signature, and investigate the functional role of the key driver gene UCN using in vitro and in vivo approaches. Methods: Integrated immunometabolic profiling was performed to identify molecular subtypes and establish a prognostic gene signature. Two distinct molecular subtypes were identified, and a 9-gene Immune Metabolic Index (IMI) was constructed. The functional role of the key driver gene UCN was investigated through in vitro functional assays and in vivo xenograft models in BALB\/c mice, including combination with PD-1 blockade. Results: Two molecular subtypes with significant survival differences (p &lt; 0.001) were identified. The established IMI demonstrated high prognostic accuracy, with Area Under the Curve (AUC) values of 0.813, 0.751, and 0.779 at 1-, 3-, and 5-year intervals, respectively. UCN was identified as the highest-risk gene in the signature. Functional assays showed that UCN silencing significantly inhibited cell proliferation and migration (p &lt; 0.05). In BALB\/c mouse xenograft models, UCN silencing remodeled the tumor microenvironment by increasing CD8+ T cell infiltration and reducing regulatory T cells (p &lt; 0.01). Furthermore, UCN knockdown significantly suppressed tumor growth and synergized with PD-1 blockade to enhance antitumor efficacy (p &lt; 0.001). Conclusions: The IMI is a robust tool for risk stratification in ccRCC. Targeting the UCN-driven immunometabolic axis represents a promising therapeutic strategy to overcome immune resistance in ccRCC.<\/jats:p>","DOI":"10.3390\/cancers18091373","type":"journal-article","created":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T19:24:51Z","timestamp":1777317891000},"page":"1373","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["An Integrated Immunometabolic Signature Predicts Prognosis and Immunotherapy Response in ccRCC and Identifies UCN-Mediated Immune Evasion as a Therapeutic Vulnerability: Evidence from In Vitro and In Vivo Studies"],"prefix":"10.3390","volume":"18","author":[{"given":"Zhinan","family":"Xia","sequence":"first","affiliation":[{"name":"Department of Urology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin 150000, China"},{"name":"Department of Urology, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu 322000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Urology, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu 322000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Radiology, Second Affiliated Hospital of Naval Medical University, Shanghai 200000, China"},{"name":"Department of Radiology, 920th Hospital of Joint Logistics Support Force, People\u2019s Liberation Army (PLA), Kunming 650000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjiao","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Urology, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu 322000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongru","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Urology, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu 322000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiyang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Urology, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu 322000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiming","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Urology, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu 322000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulan","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Urology, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu 322000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhijian","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Urology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin 150000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Urology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin 150000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiming","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Radiology, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu 322000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keliang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Urology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin 150000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3758-5172","authenticated-orcid":false,"given":"Cheng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Urology, The Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu 322000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.eururo.2025.06.005","article-title":"Epidemiology of Renal Cancer: Incidence, Mortality, Survival, Genetic Predisposition, and Risk Factors","volume":"88","author":"Larcher","year":"2025","journal-title":"Eur. 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