Stimuli-responsive nano vehicle enhances cancer immunotherapy by coordinating mitochondria-targeted immunogenic cell death and PD-L1 blockade

Induction of immunogenic cell death promotes antitumor immunity against cancer. However, majority of clinically-approved drugs are unable to elicit sufficient ICD. Here, our study revealed that mitochondria-targeted delivery of doxorubicin (DOX) massively amplified ICD via substantial generation of reactive oxygen species (ROS) after mitochondrial damage. The underlying mechanism behind increased ICD was further demonstrated to be ascribed to two pathways: (1) ROS elevated endoplasmic reticulum (ER) stress, leading to surface exposure of calreticulin; (2) ROS promoted release of various mitochondria-associated damage molecules including mitochondrial transcription factor A. Nevertheless, adaptive upregulation of PD-L1 was found after such ICD-inducing treatment. To overcome such immunosuppressive feedback, we developed a tumor stimuli-responsive nano vehicle to simultaneously exert mitochondrial targeted ICD induction and PD-L1 blockade. The nano vehicle was self-assembled from ICD-inducing copolymer and PD-L1 blocking copolymer, and possessed long-circulating property which contributed to better tumor accumulation and mitochondrial targeting. As a result, the nano vehicle remarkably activated antitumor immune responses and exhibited robust antitumor efficacy in both immunogenic and non-immunogenic tumor mouse models.

Molecular classification of endometrial cancer and its association with PD-1/PD-L1 blockade / 中国免疫学杂志

Endometrial cancer is one of the three common cancer of the female genital tract. According to the molecular char-acteristics of endometrial cancer.The cancer genome atlas proposed four molecular subtypes:POLE (DNA polymerase ε,POLE) mutant;microsatellite instability hypermutation;low copy number and high copy number/serous. Numerous preclinical and clinical researches indicated that PD-1/PD-L1 blockade therapy is a promising method for immunotherapy of endometrial cancer. The subtypes of POLE mutant and MSI hypermutation in endometrial cancers are characterized by high tumor mutation burden which may benefit from the treatment of PD-1/PD-L1 blockade. This molecular classification of endometrial cancer provides a new clinical treatment strategy for individualized immunotherapy.