{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T10:28:16Z","timestamp":1778408896177,"version":"3.51.4"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,9,5]],"date-time":"2022-09-05T00:00:00Z","timestamp":1662336000000},"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>Cuproptosis, the newly identified form of regulatory cell death (RCD), results from mitochondrial proteotoxic stress mediated by copper and FDX1. Little is known about significances of cuproptosis in oncogenesis. Here we determined clinical implications of cuproptosis in clear cell renal cell carcinoma (ccRCC). Based on the correlation and survival analyses of cuproptosis-correlated genes in TCGA ccRCC cohort, we constructed a cuproptosis-associated 13 gene signature (CuAGS-13) score system. In both TCGA training and two validation cohorts, when patients were categorized into high- and low-risk groups according to a median score as the cutoff, the CuAGS-13 high-risk group was significantly associated with shorter overall survival (OS) and\/or progression-free survival (PFS) independently (<jats:italic>P<\/jats:italic>&amp;lt;0.001 for all). The CuAGS-13 score assessment could also predict recurrence and recurrence-free survival of patients at stage I \u2013 III with a high accuracy, which outperformed the ccAccB\/ClearCode34 model, a well-established molecular predictor for ccRCC prognosis. Moreover, patients treated with immune checkpoint inhibitors (ICIs) acquired complete\/partial remissions up to 3-time higher coupled with significantly longer PFS in the CuAGS-13 low- than high-risk groups in both training and validation cohorts of ccRCCs (7.2 \u2013 14.1 <jats:italic>vs.<\/jats:italic> 2.1 \u2013 3.0 months, <jats:italic>P<\/jats:italic>&amp;lt;0.001). The combination of ICI with anti-angiogenic agent Bevacizumab doubled remission rates in CuAGS-13 high-risk patients while did not improve the efficacy in the low-risk group. Further analyses showed a positive correlation between CuAGS-13 and TIDE scores. We also observed that the CuAGS-13 score assessment accurately predicted patient response to Sunitinib, and higher remission rates in the low-risk group led to longer PFS (Low- <jats:italic>vs.<\/jats:italic> high-risk, 13.9 <jats:italic>vs.<\/jats:italic> 5.8 months, <jats:italic>P<\/jats:italic> = 5.0e-12). Taken together, the CuAGS-13 score assessment serves as a robust predictor for survival, recurrence, and response to ICIs, ICI plus anti-angiogenic drugs and Sunitinib in ccRCC patients, which significantly improves patient stratifications for precision medicine of ccRCC.<\/jats:p>","DOI":"10.3389\/fimmu.2022.971142","type":"journal-article","created":{"date-parts":[[2022,9,5]],"date-time":"2022-09-05T04:53:25Z","timestamp":1662353605000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":30,"title":["The cuproptosis-associated 13 gene signature as a robust predictor for outcome and response to immune- and targeted-therapies in clear cell renal cell carcinoma"],"prefix":"10.3389","volume":"13","author":[{"given":"Huiyang","family":"Yuan","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Qin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qingya","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yidong","family":"Fan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dawei","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,9,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21590","article-title":"Cancer statistics, 2020","volume":"70","author":"Siegel","year":"2020","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","first-page":"JCO2018792259","DOI":"10.1200\/JCO.2018.79.2259","article-title":"Renal cell carcinoma in the era of precision medicine: From molecular pathology to tissue-based biomarkers","volume":"36","author":"Signoretti","year":"2018","journal-title":"J Clin Oncol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2014.10.002","article-title":"International variations and trends in renal cell carcinoma incidence and mortality","volume":"67","author":"Znaor","year":"2015","journal-title":"Eur Urol"},{"key":"B4","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1186\/s13046-022-02382-6","article-title":"GABPA-activated TGFBR2 transcription inhibits aggressiveness but is epigenetically erased by oncometabolites in renal cell carcinoma","volume":"41","author":"Fang","year":"2022","journal-title":"J Exp Clin Cancer Res"},{"key":"B5","doi-asserted-by":"publisher","first-page":"JCO2018790147","DOI":"10.1200\/JCO.2018.79.0147","article-title":"Prognostication in kidney cancer: Recent advances and future directions","volume":"2018","author":"Graham","year":"2018","journal-title":"J Clin Oncol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1177\/1947601909359929","article-title":"Molecular stratification of clear cell renal cell carcinoma by consensus clustering reveals distinct subtypes and survival patterns","volume":"1","author":"Brannon","year":"2010","journal-title":"Genes Cancer"},{"key":"B7","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1016\/j.eururo.2014.02.035","article-title":"ClearCode34: A prognostic risk predictor for localized clear cell renal cell carcinoma","volume":"66","author":"Brooks","year":"2014","journal-title":"Eur Urol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2015.05.045","article-title":"Survival prediction of clear cell renal cell carcinoma based on gene expression similarity to the proximal tubule of the nephron","volume":"68","author":"Buttner","year":"2015","journal-title":"Eur Urol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.urolonc.2015.09.015","article-title":"Patients with ClearCode34-identified molecular subtypes of clear cell renal cell carcinoma represent unique populations with distinct comorbidities","volume":"34","author":"Haake","year":"2016","journal-title":"Urol Oncol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(15)70167-1","article-title":"A 16-gene assay to predict recurrence after surgery in localised renal cell carcinoma: development and validation studies","volume":"16","author":"Rini","year":"2015","journal-title":"Lancet Oncol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1038\/nature12222","article-title":"Cancer genome atlas research network. 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