Liao Li, Liu Yufei, Li Xianhai, Jiang Zewei, Jiang Zhijie, Yao Jing
Department of Pharmaceutics, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 210009, China.
Interventional Department, the First Affiliated Hospital of Soochow University, 899 Pinghai Avenue, Suzhou 215006, China.
ACS Appl Mater Interfaces. 2025 Apr 9;17(14):20919-20931. doi: 10.1021/acsami.5c00763. Epub 2025 Mar 30.
Effective tumor immunotherapy is hindered by an immunosuppressive tumor microenvironment (TME), especially in triple-negative breast cancer. Though phototherapy could induce immunogenic cell death (ICD) to increase antitumor immunity, the simultaneous upregulation of indoleamine 2,3-dioxygenase (IDO) induces the negative immunomodulatory effect termed as the "immune-metabolism" loop to compromise immunotherapeutic efficacy. Herein, we developed IMMGP consisting of biomimetic IND-Mn@PM (IDP) and ICG-MnO@PM (IMP), which combines the phototherapy-induced ICD and metabolic reprogramming to solve the dilemma. During the light-on phase, IMP effectively kills cancer cells with potent photodynamic ROS generation with the assistance of MnO-produced oxygen and induces ICD to reverse the immunosuppressive TME. In the light-off phase, Mn (from IDP and MnO-based redox reaction) elicits a Fenton-like reaction to relay ROS generation, which is further orchestrated with continuous exhaustion of intratumoral GSH by the conversion of Mn to Mn, and promotes dendritic cell maturation. Moreover, the released indoximod (IND) downregulated IDO to inhibit kynurenine metabolism, which reinvigorates T cell-mediated antitumor immunity. Collectively, IMMGP amplifies the immune response by breaking the "immune-metabolism" loop and sustaining the "immunologically hot" state after phototherapy, thus leading to nearly complete tumor inhibition (94.25%). Thus, IMMGP-mediated dual-phase photodynamic immunotherapy offers a novel approach in cancer nanomedicine.
有效的肿瘤免疫疗法受到免疫抑制性肿瘤微环境（TME）的阻碍，尤其是在三阴性乳腺癌中。尽管光疗可以诱导免疫原性细胞死亡（ICD）以增强抗肿瘤免疫力，但吲哚胺2,3-双加氧酶（IDO）的同时上调会诱导称为“免疫代谢”循环的负性免疫调节作用，从而损害免疫治疗效果。在此，我们开发了由仿生IND-Mn@PM（IDP）和ICG-MnO@PM（IMP）组成的IMMGP，它结合了光疗诱导的ICD和代谢重编程来解决这一困境。在光照阶段，IMP在MnO产生的氧气的协助下通过强大的光动力ROS生成有效地杀死癌细胞，并诱导ICD以逆转免疫抑制性TME。在光照关闭阶段，Mn（来自IDP和基于MnO的氧化还原反应）引发类芬顿反应以中继ROS生成，这通过将Mn转化为Mn而与肿瘤内GSH的持续消耗进一步协调，并促进树突状细胞成熟。此外，释放的吲哚莫德（IND）下调IDO以抑制犬尿氨酸代谢，从而恢复T细胞介导的抗肿瘤免疫力。总的来说，IMMGP通过打破“免疫代谢”循环并在光疗后维持“免疫活跃”状态来放大免疫反应，从而导致几乎完全的肿瘤抑制（94.25%）。因此，IMMGP介导的双相光动力免疫疗法为癌症纳米医学提供了一种新方法。
