Immunogenic Cell Death Inducing Fluorinated Mitochondria-Disrupting Helical Polypeptide Synergizes with PD-L1 Immune Checkpoint Blockade

Immunogenic cell death (ICD) is distinguished by the release of tumor-associated antigens (TAAs) and danger-associated molecular patterns (DAMPs). This cell death has been studied in the field of cancer immunotherapy due to the ability of ICD to induce antitumor immunity. Herein, endoplasmic reticulum (ER) stress-mediated ICD inducing fluorinated mitochondria-disrupting helical polypeptides (MDHPs) are reported. The fluorination of the polypeptide provides a high helical structure and potent anticancer ability. This helical polypeptide destabilizes the mitochondrial outer membrane, leading to the overproduction of intracellular reactive oxygen species (ROS) and apoptosis. In addition, this oxidative stress triggers ER stress-mediated ICD. The in vivo results show that cotreatment of fluorinated MDHP and antiprogrammed death-ligand 1 antibodies (alpha PD-L1) significantly regresses tumor growth and prevents metastasis to the lungs by activating the cytotoxic T cell response and alleviating the immunosuppressive tumor microenvironment. These results indicate that fluorinated MDHP synergizes with the immune checkpoint blockade therapy to eliminate established tumors and to elicit antitumor immune responses.

Automated summary

The study demonstrates the potential of fluorinated mitochondria-disrupting helical polypeptides (MDHPs) in inducing immunogenic cell death (ICD) and activating antitumor immune responses. By destabilizing the mitochondrial outer membrane and triggering excessive ROS production and apoptosis, the helical polypeptide leads to ER stress-mediated ICD. The combination therapy of fluorinated MDHP and anti-PD-L1 antibodies shows promising results in regression of tumor growth and prevention of metastasis, suggesting a synergistic effect with immune checkpoint blockade therapy.