Pheophorbide A–Mediated Photodynamic Therapy Potentiates Checkpoint Blockade Therapy of Tumor with Low PD–L1 Expression

Although the immune checkpoint blockade (ICB) has made a great success in cancer immunotherapy, the overall response rate to the ICB, such as anti–programmed death ligand 1 (PD–L1) therapy, remains only at 20–30%. One major reason is the low expression level of the immune checkpoint in a certain type of tumor cells and its insufficient activation of the host immune system. Herein, we reported a cyclic RGD (cRGD)–modified liposomal delivery system loading the anti–PD–L1 antibody and the photosensitizer pheophorbide A (Pa), allowing a targeting of the low PD–L1 expressing 4T1 mouse breast cancer cells through the recognition of an overexpression of α(v)β(3) integrin on the tumor cells. The Pa–mediated photodynamic therapy (PDT) elevated the expression of PD–L1 on the tumor cells. PDT, in combination with the anti–PD–L1 therapy, promoted the activation and maturation of dendritic cells as well as the infiltration of cytotoxic T lymphocytes, resulting in the augmented antitumor immune response for the enhanced therapeutic effect. These results demonstrated the combined therapeutic effects of PDT and ICB on the tumor with low PD–L1 levels. Our study suggested that an increase in the PD–L1 expression in tumor cells by PDT would be a promising adjuvant treatment to overcome the ICB irresponsiveness.