Cytokine-induced killer (CIK) Cells-associated transcriptome signature reveals the potential immunomodulatory role of TNFSF14 in clear cell renal cell carcinoma.

Among adoptive immune cell therapies, cytokine-induced killer cell (CIK) therapy has demonstrated clear therapeutic relevance in multiple cancers, particularly clear cell renal cell carcinoma (ccRCC). 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.