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

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.