Immune Checkpoint-Modulating Photosensitizer That Targets BRD4 for Cancer Photoimmunotherapy

Photodynamic therapy is an efficient approach to promote cytotoxic T lymphocyte tumor infiltration to convert immunologically cold tumors into hot tumors through the induction of immunogenic cell death . However, tumors usually overexpress immune checkpoints such as PD-L1 to suppress T lymphocyte antitumor activity and evade immune surveillance. Therefore, the design of efficient photosensitizers to overcome checkpoint-mediated immune evasion is highly necessary. In this work, we report the design of <b>BRD-PS</b>, a BRD4-targeting photosensitizer, as a new class of immunomodulatory photosensitizer termed an immune checkpoint-modulating photosensitizer, to solve this issue. On one hand, <b>BRD-PS</b> induces immunogenic pyroptosis and ferroptosis to promote the activation and tumor infiltration of cytotoxic T cells. On the other hand, <b>BRD-PS</b> suppresses the expression of PD-L1 to avoid immune evasion. This work demonstrated the feasibility of utilizing a single photosensitizer to simultaneously induce immunogenic cell death and PD-L1 downregulation for synergistic cancer photoimmunotherapy.