Integrative pan-cancer and clinical cytokine profiling reveals a pro-inflammatory cytokine index for colon cancer peritoneal metastasis and immunotherapy response

Background Cytokines are central to tumor immunity, yet their landscape and clinical utility across cancer types remain incompletely characterized. Methods We selected a representative cytokine panel covering Th1/Th2/Th17, pro-inflammatory, regulatory, and chemokine functions. Using TCGA pan-cancer data, we derived a transcriptomic cytokine index (gCCI) as the difference between pro-tumor and anti-tumor ssGSEA scores and evaluated its associations with prognosis, immune microenvironment, and immunotherapy response. We further validated a protein-level cytokine index (pCCI) using the same formula in an independent cohort of 183 cytokine profiling assays from colorectal cancer patients. Results The gCCI effectively distinguished tumor from normal tissue in colorectal cancer and stratified survival in multiple cancer types. High gCCI was associated with activated inflammatory pathways by GSEA and showed cancer-type-specific correlations with MSI, TMB, and immune cell infiltration. Notably, low gCCI correlated with better immunotherapy response and prolonged survival in two independent cohorts. In protein-level validation, pCCI was significantly associated with T stage, N stage, M stage, and tumor location (all p < 0.05), with M1c (peritoneal metastasis) showing the highest pCCI levels among M substages. Dichotomized analysis by median pCCI further revealed that high pCCI was significantly enriched in colon cancer patients with M1c, whereas no such associations were observed in rectal cancer. Conclusions The cytokine index, at both transcriptomic and protein levels, is associated with prognosis and immunotherapy response, with its utility being cancer-type and site-specific. Its particular relevance to colon cancer and peritoneal metastasis warrants further validation in prospective studies.