Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province 250012, P. R. China.
Key Laboratory of Chemical Biology (Ministry of Education), Department of Pharmacology, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, P. R. China.
J Med Chem. 2024 Nov 14;67(21):18930-18942. doi: 10.1021/acs.jmedchem.4c01362. Epub 2024 Oct 24.
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 , a BRD4-targeting photosensitizer, as a new class of immunomodulatory photosensitizer termed an immune checkpoint-modulating photosensitizer, to solve this issue. On one hand, induces immunogenic pyroptosis and ferroptosis to promote the activation and tumor infiltration of cytotoxic T cells. On the other hand, 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.
光动力疗法是一种有效的方法，可以通过诱导免疫原性细胞死亡，促进细胞毒性 T 淋巴细胞浸润肿瘤，将免疫原性冷肿瘤转化为热肿瘤。然而，肿瘤通常过度表达免疫检查点，如 PD-L1，以抑制 T 淋巴细胞抗肿瘤活性并逃避免疫监视。因此，设计高效的光敏剂来克服检查点介导的免疫逃逸是非常必要的。在这项工作中，我们报告了 BRD4 靶向光敏剂 的设计，作为一类新的免疫调节光敏剂，称为免疫检查点调节光敏剂，以解决这个问题。一方面， 通过诱导免疫原性细胞焦亡和铁死亡，促进细胞毒性 T 细胞的激活和肿瘤浸润。另一方面， 抑制 PD-L1 的表达，以避免免疫逃逸。这项工作证明了利用单一光敏剂同时诱导免疫原性细胞死亡和 PD-L1 下调以实现协同癌症光免疫治疗的可行性。
