Cordycepin Targets HRD1 to Promote Cancer Cell PD‐L1 Ubiquitin–Proteasome Degradation and Increase Antitumor Immunity

ABSTRACT Immune checkpoint blockade has become an effective strategy for inhibiting tumor growth, especially immune checkpoint inhibitors that target the programmed death 1 (PD‐1)/programmed death‐ligand 1 (PD‐L1) pathway, which have shown significant effects in tumor immunotherapy. In this study, we found that naturally sourced Cordyceps militaris extract can effectively downregulate the protein expression level of PD‐L1 in human colorectal cancer cell lines. Further systematic isolation, purification, and analysis of its active components revealed that cordycepin (COR) is the key active molecule mediating PD‐L1 degradation. Mechanistically, COR specifically and selectively targets the ubiquitin E3 ligase HMG‐CoA reductase degradation protein 1, thus promoting the degradation of PD‐L1 protein through the ubiquitin–proteasome pathway. This process significantly enhances the cytotoxic killing effect of effector T lymphocytes against colorectal cancer cells, ultimately achieving robust antitumor effects. Furthermore, this study also revealed that COR exhibits potential synergistic therapeutic effects when combined with anti‐CTLA4 antibodies in preclinical tumor treatment. In summary, COR, as the primary bioactive component of Cordyceps militaris , demonstrates considerable potential to act as a small‐molecule immune checkpoint modulator and inhibitor, thereby providing a novel therapeutic strategy for the immunotherapy of colorectal cancer.