{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T14:22:54Z","timestamp":1791901374787,"version":"4.3.4"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T00:00:00Z","timestamp":1756684800000},"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:sec><jats:title>Background<\/jats:title><jats:p>Necroptosis plays a critical role in the onset and progression of numerous malignancies, with colorectal cancer (CRC) ranking among the leading causes of cancer-related mortality worldwide. However, the relationship between necroptosis-related genes (NRGs) and CRC remains contentious. Hence, this study aims to develop a novel NRG-based signature to predict the prognosis of CRC patients and explore its potential role.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Transcriptome data from the Gene Expression Omnibus (GEO) databases and the Cancer Genome Atlas (TCGA) were employed to identify cancer hallmarks associated with outcomes in CRC. A novel NRG signature was formulated and validated using least absolute shrinkage and selection operator (LASSO) regression analysis and COX regression analysis. Subsequently, univariate and multivariate Cox regression analyses, Kaplan-Meier (K-M) survival analysis, receiver operating characteristic (ROC) curves, and nomograms were utilized to assess the predictive capability of our signature. Furthermore, a variety of bioinformatics analysis algorithms were leveraged to uncover potential mechanisms, tumor immune status, and differences in drug sensitivity between the two-risk groups. The expression of signature NRGs in CRC was evaluated through quantitative reverse transcription polymerase chain reaction (qRT-PCR).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A novel signature consisting of eighteen NRGs (CTSB, PAEP, ARL4C, TAP2, WFS1, BATF2, DUSP27, CXCL9, EPHB2, IRF8, CXCL13, GZMB, APOL6, NLRC5, CXCL10, IRF1, HES6, and PTGDR) was successfully established. This signature displayed consistent predictive performance and general applicability for CRC, as validated across three independent cohorts. Moreover, stromal and immune cells within the tumor microenvironment (TME) were found to be correlated with necroptosis. Additionally, notable differences in the sensitivity to anti-tumor agents were observed between the two groups. The qRT-PCR results indicated aberrant expression of these signature NRGs in CRC.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>NRG was proved to be an accurate predictor of CRC prognosis. Furthermore, the novel signature exhibited consistent value and translational potential for predicting prognosis, tumor immunogenicity, and therapeutic response in CRC.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1619749","type":"journal-article","created":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T05:30:33Z","timestamp":1756704633000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Role of necroptosis-related genes in immune activity and prognosis of colorectal cancer"],"prefix":"10.3389","volume":"16","author":[{"given":"Lulu","family":"Tan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuaifeng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weilong","family":"Chang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoying","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huifang","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiwei","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huifen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yudie","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhibo","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuyan","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyuan","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,9,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","first-page":"e0256020","DOI":"10.1371\/journal.pone.0256020","article-title":"Novel diagnostic and prognostic biomarkers of colorectal cancer: Capable to overcome the heterogeneity-specific barrier and valid for global applications","volume":"16","author":"Hameed","year":"2021","journal-title":"PloS One"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/nature10868","article-title":"Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR","volume":"483","author":"Prahallad","year":"2012","journal-title":"Nature"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.652394","article-title":"Metastatic colorectal cancer patient with microsatellite stability and BRAF(V600E) mutation showed a complete metabolic response to PD-1 blockade and bevacizumab: A case report","volume":"11","author":"Fang","year":"2021","journal-title":"Front Oncol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.852927","article-title":"Molecular network of colorectal cancer and current therapeutic options","volume":"12","author":"Huang","year":"2022","journal-title":"Front Oncol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2011.39.4692","article-title":"Optimal colorectal cancer staging criteria in TNM classification","volume":"30","author":"Ueno","year":"2012","journal-title":"J Clin Oncol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22105246","article-title":"Heterogeneity of colorectal cancer progression: molecular gas and brakes","volume":"22","author":"Gaiani","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2016.8","article-title":"Cancer therapy in the necroptosis era","volume":"23","author":"Su","year":"2016","journal-title":"Cell Death Differ"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio711","article-title":"Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury","volume":"1","author":"Degterev","year":"2005","journal-title":"Nat Chem Biol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1310050","article-title":"Necroptosis","volume":"370","author":"Linkermann","year":"2014","journal-title":"N Engl J Med"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2009.12.003","article-title":"Necroptosis as an alternative form of programmed cell death","volume":"22","author":"Christofferson","year":"2010","journal-title":"Curr Opin Cell Biol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pathol-052016-100247","article-title":"Necroptosis: mechanisms and relevance to disease","volume":"12","author":"Galluzzi","year":"2017","journal-title":"Annu Rev Pathol"},{"key":"B13","doi-asserted-by":"crossref","DOI":"10.1016\/j.bbcan.2019.01.006","article-title":"The role of necroptosis in cancer: A double-edged sword","volume":"1871","author":"Qin","year":"2019","journal-title":"Biochim Biophys Acta Rev Cancer"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/cr.2015.56","article-title":"Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics","volume":"25","author":"Koo","year":"2015","journal-title":"Cell Res"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1126\/science.aad0395","article-title":"RIPK1 and NF-kappaB signaling in dying cells determines cross-priming of CD8(+) T cells","volume":"350","author":"Yatim","year":"2015","journal-title":"Science"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.04.032","article-title":"The tumor suppressor hace1 is a critical regulator of TNFR1-mediated cell fate","volume":"15","author":"Tortola","year":"2016","journal-title":"Cell Rep"},{"key":"B17","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1038\/s41586-018-0519-y","article-title":"Necroptosis microenvironment directs lineage commitment in liver cancer","volume":"562","author":"Seehawer","year":"2018","journal-title":"Nature"},{"key":"B18","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1186\/s12943-019-1029-8","article-title":"The role of necroptosis in cancer biology and therapy","volume":"18","author":"Gong","year":"2019","journal-title":"Mol Cancer"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-17-3962","article-title":"A RIPK3-PGE(2) circuit mediates myeloid-derived suppressor cell-potentiated colorectal carcinogenesis","volume":"78","author":"Yan","year":"2018","journal-title":"Cancer Res"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.56152","article-title":"MLKL inhibits intestinal tumorigenesis by suppressing STAT3 signaling pathway","volume":"17","author":"Zhao","year":"2021","journal-title":"Int J Biol Sci"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-021-03947-y","article-title":"RIPK3 signaling and its role in the pathogenesis of cancers","volume":"78","author":"Liu","year":"2021","journal-title":"Cell Mol Life Sci"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.607622","article-title":"Identification and verification of immune-related gene prognostic signature based on ssGSEA for osteosarcoma","volume":"10","author":"Xiao","year":"2020","journal-title":"Front Oncol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2015.12.004","article-title":"The Molecular Signatures Database (MSigDB) hallmark gene set collection","volume":"1","author":"Liberzon","year":"2015","journal-title":"Cell Syst"},{"key":"B24","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1186\/1471-2105-9-559","article-title":"WGCNA: an R package for weighted correlation network analysis","volume":"9","author":"Langfelder","year":"2008","journal-title":"BMC Bioinf"},{"key":"B25","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc Natl Acad Sci U.S.A"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2023.1170737","article-title":"A novel signature combing cuproptosis- and ferroptosis-related genes in sepsis-induced cardiomyopathy","volume":"14","author":"Song","year":"2023","journal-title":"Front Genet"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1022420","article-title":"A necroptosis related prognostic model of pancreatic cancer based on single cell sequencing analysis and transcriptome analysis","volume":"13","author":"Chen","year":"2022","journal-title":"Front Immunol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"2227491","DOI":"10.1080\/16078454.2023.2227491","article-title":"A novel necroptosis-related gene signature in acute myeloid leukemia","volume":"28","author":"Fang","year":"2023","journal-title":"Hematology"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.682002","article-title":"Identification of CDK2-related immune forecast model and ceRNA in lung adenocarcinoma, a pan-cancer analysis","volume":"9","author":"Liu","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.2147\/CMAR.S272797","article-title":"Development and validation of nomograms for predicting cancer-specific survival in elderly patients with intrahepatic cholangiocarcinoma after liver resection: A competing risk analysis","volume":"12","author":"Wang","year":"2020","journal-title":"Cancer Manag Res"},{"key":"B31","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1186\/s13059-017-1349-1","article-title":"xCell: digitally portraying the tissue cellular heterogeneity landscape","volume":"18","author":"Aran","year":"2017","journal-title":"Genome Biol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.676485","article-title":"The pyroptosis-related signature predicts prognosis and indicates immune microenvironment infiltration in gastric cancer","volume":"9","author":"Shao","year":"2021","journal-title":"Front Cell Dev Biol"},{"key":"B33","article-title":"Pyroptosis-related gene signature elicits immune response in rosacea","author":"Hu","year":"2023","journal-title":"Exp Dermatol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"105644","DOI":"10.1016\/j.phrs.2021.105644","article-title":"In silico development and clinical validation of novel 8 gene signature based on lipid metabolism related genes in colon adenocarcinoma","volume":"169","author":"Jiang","year":"2021","journal-title":"Pharmacol Res"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.7150\/thno.32126","article-title":"RIP3 promotes colitis-associated colorectal cancer by controlling tumor cell proliferation and CXCL1-induced immune suppression","volume":"9","author":"Liu","year":"2019","journal-title":"Theranostics"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-21-0772","article-title":"Spatial organization and prognostic significance of NK and NKT-like cells via multimarker analysis of the colorectal cancer microenvironment","volume":"10","author":"Vayrynen","year":"2022","journal-title":"Cancer Immunol Res"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-18-0481","article-title":"Lactate-mediated acidification of tumor microenvironment induces apoptosis of liver-resident NK cells in colorectal liver metastasis","volume":"7","author":"Harmon","year":"2019","journal-title":"Cancer Immunol Res"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2022.05.024","article-title":"Perioperative arginine prevents metastases by accelerating natural killer cell recovery after surgery","volume":"30","author":"Angka","year":"2022","journal-title":"Mol Ther"},{"key":"B39","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1186\/s12915-021-01068-3","article-title":"Rac1\/ROCK-driven membrane dynamics promote natural killer cell cytotoxicity via granzyme-induced necroptosis","volume":"19","author":"Zhu","year":"2021","journal-title":"BMC Biol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2019.05.034","article-title":"MLKL attenuates colon inflammation and colitis-tumorigenesis via suppression of inflammatory responses","volume":"459","author":"Zhao","year":"2019","journal-title":"Cancer Lett"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.814621","article-title":"The expression pattern of hypoxia-related genes predicts the prognosis and mediates drug resistance in colorectal cancer","volume":"10","author":"Yuan","year":"2022","journal-title":"Front Cell Dev Biol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24021516","article-title":"Identification of aging and young subtypes for predicting colorectal cancer prognosis and immunotherapy responses","volume":"24","author":"Tan","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.57164","article-title":"Ferroptosis-related Genes for Overall Survival Prediction in Patients with Colorectal Cancer can be Inhibited by Gallic acid","volume":"17","author":"Hong","year":"2021","journal-title":"Int J Biol Sci"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1085038","article-title":"Integrated analysis of necroptosis-related genes for evaluating immune infiltration and colon cancer prognosis","volume":"13","author":"Yang","year":"2022","journal-title":"Front Immunol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2022.909245","article-title":"Necroptosis-related genes associated with immune activity and prognosis of colorectal cancer","volume":"13","author":"Peng","year":"2022","journal-title":"Front Genet"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1619749\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,1]],"date-time":"2025-09-01T05:30:34Z","timestamp":1756704634000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1619749\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,1]]},"references-count":45,"alternative-id":["10.3389\/fimmu.2025.1619749"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1619749","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,1]]},"article-number":"1619749"}}