Cordycepin mediates pyroptosis in HCC through the upregulation of TXNIP and synergizes with anti–PD-L1 immunotherapy

Background: Immune checkpoint inhibitors are effective treatments for HCC; however, their therapeutic efficacy is often limited by the development of drug resistance. Therefore, investigating new combination therapeutics involving immune checkpoint inhibitors is critical to improving patient prognosis. In this study, we investigated the therapeutic effect of cordycepin (COR) in HCC and its synergistic effect with anti–programmed cell death ligand 1 (anti–PD-L1) immunotherapy. Methods: We selected 2 HCC cell lines to investigate the effects of COR on HCC growth using in vivo and in vitro experiments. We performed RNA sequencing of the MHCC97H cell line treated with or without COR to understand the underlying mechanism and identify the key regulatory genes. Through in vivo and in vitro experiments on gene knockdown cells, we identified thioredoxin-interacting protein as a key molecule involved in the role of COR. Next, we used mouse subcutaneous and orthotopic tumor models to evaluate the therapeutic effects of COR, atezolizumab (a programmed death-ligand 1 [PD-L1] inhibitor), or their combination. Multiple immunofluorescence staining revealed that the combination of atezolizumab and COR therapy greatly increased the number of tumor-infiltrating CD8 + T cells and PD-L1 expression in HCC compared to monotherapy. Results: Our study revealed that COR significantly inhibited HCC growth both in vitro and in vivo. Mechanistically, we showed that COR induces endoplasmic reticulum stress, which upregulates thioredoxin-interacting protein expression and leads to HCC cell pyroptosis. In addition, the combination treatment with COR and PD-L1 inhibitors profoundly inhibited HCC. Conclusions: Overall, our study successfully established a combined therapeutic strategy using COR and PD-L1 inhibitors. This strategy has significant synergistic effects on cancer cells, highlighting its importance in cancer therapy.