A Cytokine-Related Gene Signature for Pan-Cancer Prognostic Stratification and Malignant Phenotype Characterization

Cytokines are central regulators of inflammation and immune responses within the tumor microenvironment and have been implicated in cancer progression and prognosis. However, the prognostic value of coordinated cytokine-related transcriptional programs across cancer types has not been systematically explored. Pan-cancer transcriptomic and clinical data were analyzed to construct a cytokine-related prognostic signature using least absolute shrinkage and selection operator (LASSO) Cox regression. Patients were stratified into high-risk and low-risk groups based on the derived risk score. Prognostic performance was evaluated in training and test cohorts, and biological relevance was assessed through survival analyses and pathway-level investigations. A 16-gene cytokine-related signature was established that consistently stratified patients into distinct prognostic groups across multiple cancer types. High cytokine-related risk scores were significantly associated with unfavorable survival outcomes and were linked to enhanced cell cycle activity, epithelial-mesenchymal transition, and extracellular matrix remodeling. Integration of the risk score with clinical variables improved individualized survival prediction. Immunohistochemical analyses further confirmed increased protein expression of representative risk-associated genes, including pannexin 1 (PANX1) and FERM domain containing 8 (FRMD8), in multiple tumor tissues compared with corresponding normal tissues. The cytokine-related prognostic signature captures key inflammatory and immune-related programs underlying tumor aggressiveness and provides a robust tool for pan-cancer risk stratification with potential clinical utility.