Disruption of Ferroptosis Inhibition and Immune Evasion with Tumor‐Activatable Prodrug for Boosted Photodynamic/Chemotherapy Eradication of Drug‐Resistant Tumors

Breast cancer is a malignant tumor that threatens the life and health of women worldwide. As the first-line chemotherapy drug for breast cancer, doxorubicin (DOX) can inhibit the synthesis of RNA and DNA, and it exhibits strong inhibitory activity against breast cancer. However, drug-induced systemic toxicity and drug resistance can occur with DOX treatment. In this work, TSPO protein is identified as a promising target for overcoming drug resistance and we designed a novel BT-DOX/PDP conjugate to solve these problems in drug chemotherapy. It is found that BT-DOX/PDP can effectively downregulate TSPO1 protein and sensitize MCF-7/Adr to DOX. Furthermore, due to its positive charge, BT-DOX/PDP is readily loaded into puerarin (PUE), the resulting BT-DOX/PDP@PUE exhibited minimal systemic toxicity but enhanced antitumor activity in animal models, as compared with BT-DOX/PDP. This study demonstrates the advantages of combined chemotherapy and photodynamic therapy in overcoming drug resistance, which may be applied in the design of other photodynamic therapy-based conjugates to enhance antitumor therapy.