Mitochondrial-targeted brequinar liposome boosted mitochondrial-related ferroptosis for promoting checkpoint blockade immunotherapy in bladder cancer

Checkpoint blockade immunotherapy (CBI) have exhibited remarkable benefits for cancer therapy. However, the low responsivity of CBI hinders its application in treatment of bladder cancer. Ferroptosis shows potential for increasing the responsivity of CBI by inducing immunogenic cell death (ICD) process. Herein, we developed a mitochondrial-targeted liposome loaded with brequinar (BQR) (BQR@MLipo) for enhancing the mitochondrial-related ferroptosis in bladder cancer in situ. It could be found that BQR@MLipo could selectively accumulate into mitochondria and inactivate dihydroorotate dehydrogenase (DHODH), which induced extensive mitochondrial lipid peroxidation and ROS, finally triggering ferroptosis of bladder cancer cells to boost the release of intracellular damage-associated molecular patterns (DAMPs) such as calreticulin (CRT), adenosine triphosphate (ATP), high mobility group box 1 (HMGB1). In addition, BQR@MLipo further promoted the release of mtDNA into the cytoplasm to activate the cGAS-STING pathway for the secretion of IFN-β, which would increase the cross-presentation of antigens by dendritic cells and macrophage phagocytosis. Furthermore, the in vivo studies revealed that BQR@MLipo could remarkably accumulate into the bladder tumor and successfully initiate the infiltration of CD8+ T cells into tumor microenvironment for enabling efficient CBI to inhibit bladder tumor growth. Therefore, BQR@MLipo may represent a clinically promising modality for enhancing CBI in bladder tumor.