Immune Checkpoint-Modulating\nPhotosensitizer That\nTargets BRD4 for Cancer Photoimmunotherapy

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