Chaperonin containing TCP1 subunit 5 as a novel pan-cancer prognostic biomarker for tumor stemness and immunotherapy response: insights from multi-omics data, integrated machine learning, and experimental validation.

BACKGROUND: Chaperonin containing TCP1 subunit 5 (CCT5), a vital component of the molecular chaperonin complex, has been implicated in tumorigenesis, cancer stemness maintenance, and therapeutic resistance. Nevertheless, its comprehensive roles in pan-cancer progression, underlying biological functions, and potential as a predictor of immunotherapy response remains poorly understood. METHODS: We performed a comprehensive multi-omics pan-cancer analysis of CCT5 across 33 cancer types, integrating bulk RNA-seq, single-cell RNA-seq (scRNA-seq), and spatial transcriptomics data. CCT5 expression patterns, prognostic relevance, stemness association, and immune microenvironment relationships were evaluated. A novel CCT5-based signature (CCT5.Sig) was developed using machine learning on 23 immune checkpoint blockade (ICB) cohorts (n = 1394) spanning eight cancer types. Model performance was assessed using AUC metrics and survival analyses. RESULTS: CCT5 was significantly overexpressed in tumor tissues and primarily localized to malignant and cycling cells. High CCT5 expression correlated with poor prognosis in multiple cancers and was enriched in oncogenic, cell cycle, and DNA damage repair pathways. CCT5 expression was positively associated with mRNAsi, mDNAsi, and CytoTRACE scores, indicating a role in stemness maintenance. Furthermore, CCT5-high tumors exhibited immune-cold phenotypes, with reduced TILs and CD8⁺ T cell activity. The CCT5.Sig model, based on genes co-expressed with CCT5, achieved superior predictive accuracy for ICB response (AUC = 0.82 in validation and 0.76 in independent testing), outperforming existing pan-cancer signatures. CONCLUSION: This study reveals the multifaceted oncogenic roles of CCT5 and highlights its potential as a pan-cancer biomarker for prognosis and immunotherapy response. The machine learning-derived CCT5.Sig model provides a robust tool for patient stratification and may inform personalized immunotherapy strategies.