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

ABSTRACT Background 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. Methods 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. Results 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. Conclusion 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.