Pan-cancer multi-omics analysis of CCT4 in tumor progression and cancer immunity, with focus on lung adenocarcinoma

Yonghui Wu¹Zhenpeng Wu²Junjie Wen³Desheng Zhou^1*

• ¹Afiliated Hospital Shenzhen Baoan Central Hospital of Guangdong Medical University, Shenzhen, China
• ²Department of Dermatology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
• ³State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

Background Efficient proteostasis and immune evasion are both critical for tumor progression. The chaperonin TRiC/CCT complex, which mediates the folding of cytoskeletal and signaling proteins, has been associated with oncogenesis; however, the specific role of its subunit CCT4 in tumor–immune interactions remain unclear. Methods To address this gap, we integrated transcriptomics, proteomics, genomics, epigenetics and immunogenomics data. A comprehensive pan-cancer analysis was conducted (including the expression patterns, clinical relevance, prognosis value, immune infiltration of pan-cancer). Then an in-depth analysis of lung adenocarcinoma (LUAD) was carried out through enrichment analysis and single-cell RNA sequencing, and verified through in vitro cell experiments. Results CCT4 was found to be aberrantly upregulated across a majority of tumor types, particularly in LUAD, where elevated expression was associated with advanced stage and inferior survival outcomes. High CCT4 levels were linked to reduced immune cell infiltration and diminished anti-tumor immune signaling, specifically manifested as increased Th2 cell infiltration and decreased Th1 and CD8⁺ T-cell signatures. Single-cell analyses revealed coordinated overexpression of all CCT subunits in tumor epithelial cells, supporting a global TRiC activation. However, CCT4 was preferentially enriched within highly proliferative subclusters, suggesting partial subunit-specific regulation. CCT4 knockdown suppressed LUAD cell proliferation, migration, and invasion in vitro. Conclusions CCT4 links enhanced proteostasis with immune evasion in LUAD, acting partly through TRiC complex activity and possibly through independent nuclear functions. These findings refine the understanding of how proteostatic machinery contributes to immune modulation in cancer and highlight CCT4 as a potential molecular node bridging tumor growth and immune suppression.