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Despite being clinically successful, the molecular signatures associated with the immune-regulatory role of these CIK cells in cancers remain elusive. Considering this, we systematically identified CIK expansion-induced genes (CIK-EIGs) from their transcriptome profiles and curated the CIK-EIG-anchored transcriptome framework across bulk and single-cell ccRCC datasets. Using comprehensive bioinformatics analysis, we next developed the CIK-EIG-anchored risk stratification (CIKRRS), which enabled reliable prediction of patient prognosis, correlated with the clinical-pathological course, and defined an immunologically inflamed but clinically unfavorable phenotype. Of interest, the integrative analyses highlighted TNFSF14 as one of the key functional modulators within the CIK-EIG-associated immune landscape, showing a strong association with cytotoxic immune signaling and cancer-immunity cycle activity. Subsequently, the functional assays verified that TNFSF14 significantly enhanced CIK-mediated tumor cell killing, degranulation, and cytokine production in ccRCC cell lines, confirming its role in enhancing CIK effector function. Taken together, our findings present a CIK-EIG-anchored transcriptomic and prognostic framework and highlight the potential relevance of TNFSF14 for further optimization of CIK-based immunotherapy in ccRCC patients.<\/jats:p>","DOI":"10.1007\/s00262-026-04422-y","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T05:15:22Z","timestamp":1779254122000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Cytokine-induced killer (CIK) Cells-associated transcriptome signature reveals the potential immunomodulatory role of TNFSF14 in clear cell renal cell carcinoma"],"prefix":"10.1007","volume":"75","author":[{"given":"Yinhao","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linli","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyue","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yutao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Fitria","family":"Setiawan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronika","family":"Lukacs-Kornek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Ritter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amit","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ingo G. 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