CCT2 Promotes Immune Escape in Colorectal Cancer by Regulating the JAK1-STAT3-PD-L1 Axis

Colorectal cancer (CRC) is a major global health burden. While immune checkpoint inhibitors have greatly advanced cancer therapy, their therapeutic effects are unsatisfactory in microsatellite-stable/proficient mismatch repair CRC. This study explored the molecular mechanisms underlying CRC immune evasion.

Bioinformatics analysis and machine learning were applied to screen key targets. Real-time quantitative polymerase chain reaction (RT-PCR) detected CCT2 and programmed cell death ligand 1 (PD-L1) mRNA levels, and Western blot measured PD-L1, STAT3, and p-STAT3 protein expressions. Cell proliferation, apoptosis, invasion, migration, and immune cytotoxicity were assessed via 5-ethynyl-2'-deoxyuridine (EdU), TUNEL, Transwell, wound healing, and lactate dehydrogenase (LDH) assays. ELISA was used to detect interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α) secretion, and xenograft mouse models were established for in vivo verification, with immunohistochemistry detecting tumor PD-L1 expression.

This study identified CCT2 as a core gene of CRC. Analysis of public datasets revealed a significant increase in CCT2 expression in CRC tissues. CCT2 knockdown inhibited CRC cell growth, invasiveness, and migration in vitro and in vivo. A positive correlation between CCT2 and PD-L1 expression was observed in public and clinical CRC patients. Furthermore, CCT2 knockdown promoted the activation and proinflammatory cytokine secretion of CD8⁺ T cells. Mechanistically, CCT2 knockdown diminished PD-L1 expression and promoted activation of CD8⁺ T cells via the JAK1-STAT3 signaling pathway.

CCT2 upregulation promoted immune escape of colorectal cancer via regulating the JAK1-STAT3-PD-L1 axis, suggesting a promising role of CCT2 in CRC treatment.