Guangdong Second Provincial General Hospital, Postdoctoral Research Station of Basic Medicine, School of Medicine, Jinan University, Xingangzhong Road 466, Guangzhou 518037, PR China.
State Key Laboratory of Rare Earth Resource Utilization, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Renmin Street 5625, Changchun 130012, PR China.
Acta Biomater. 2024 Sep 15;186:383-395. doi: 10.1016/j.actbio.2024.07.034. Epub 2024 Jul 26.
Immunotherapy can enhance primary tumor efficacy, restrict distant growth, and combat lung metastasis. Unfortunately, it remains challenging to effectively activate the immune response. Here, tertiary butyl, methoxy, and triphenylamine (TPA) were utilized as electron donors to develop multifunctional photosensitizers (PSs). CNTPA-TPA, featuring TPA as the donor (D) and cyano as the acceptor (A), excelled in reactive oxygen species (ROS) generation due to its smaller singlet-triplet energy gap (ΔE) and larger spin-orbit coupling constant (SOC). Additionally, cyano groups reacted with glutamate (Glu) and glutathione (GSH), reducing intracellular GSH levels. This not only enhanced PDT efficacy but also triggered redox dyshomeostasis-mediated ferroptosis. The positive effects of photodynamic therapy (PDT) and ferroptosis promoted immunogenic cell death (ICD) and immune activation. By further combining anti-programmed cell death protein ligand-1 (anti-PD-L1) antibody, the powerful treatments of ferroptosis-assisted photodynamic immunotherapy significantly eradicated the primary tumors, inhibited the growth of distant tumors, and suppressed lung metastasis. In this study, a three-pronged approach was realized by single-component CNTPA-TPA, which simultaneously served as metal-free ferroptosis inducers, type-I photosensitizers, and immunologic adjuvants for near-infrared fluorescence imaging (NIR FLI)-guided multimodal phototheranostics of tumor. STATEMENT OF SIGNIFICANCE: (1) CNTPA-TPA shared the smallest singlet-triplet energy gap and the largest spin-orbit coupling constant, which boosted intersystem crossing for efficient type-I photodynamic therapy (PDT); (2) Special reactions between cyano groups with glutamate and glutathione in mild conditions restricted the biosynthesis of intracellular GSH. GSH-depletion efficiently induced glutathione peroxidase 4 inactivation and lipid peroxide, resulting in ferroptosis of tumor cells; (3) The combination treatments of ferroptosis-assisted photodynamic immunotherapy induced by single-component CNTPA-TPA with the participation of anti-PD-L1 antibody resulted in increased T-cell infiltration and profound suppression of both primary and distant tumor growth, as well as lung metastasis.
免疫疗法可以增强原发性肿瘤的疗效，限制远处生长，并对抗肺转移。不幸的是，有效地激活免疫反应仍然具有挑战性。在这里，叔丁基、甲氧基和三苯胺（TPA）被用作电子供体来开发多功能光敏剂（PSs）。CNTPA-TPA 以 TPA 为供体（D）和氰基为受体（A），由于其较小的单重态-三重态能量差（ΔE）和较大的自旋轨道耦合常数（SOC），在产生活性氧物种（ROS）方面表现出色。此外，氰基与谷氨酸（Glu）和谷胱甘肽（GSH）反应，降低细胞内 GSH 水平。这不仅增强了 PDT 的疗效，还引发了氧化还原失衡介导的铁死亡。光动力疗法（PDT）和铁死亡的积极作用促进了免疫原性细胞死亡（ICD）和免疫激活。通过进一步结合抗程序性细胞死亡蛋白配体-1（抗 PD-L1）抗体，铁死亡辅助光动力免疫治疗的强大治疗作用显著根除了原发性肿瘤，抑制了远处肿瘤的生长，并抑制了肺转移。在这项研究中，通过单一组分 CNTPA-TPA 实现了三管齐下的方法，该方法同时作为无金属铁死亡诱导剂、I 型光敏剂和免疫佐剂，用于近红外荧光成像（NIR FLI）引导的肿瘤多模式光疗。意义声明：（1）CNTPA-TPA 具有最小的单重态-三重态能量差和最大的自旋轨道耦合常数，促进了高效的 I 型光动力疗法（PDT）的电子系间穿越；（2）在温和条件下，氰基与谷氨酸和谷胱甘肽之间的特殊反应限制了细胞内 GSH 的生物合成。GSH 耗竭有效地诱导谷胱甘肽过氧化物酶 4 失活和脂质过氧化物，导致肿瘤细胞发生铁死亡；（3）由单一组分 CNTPA-TPA 与抗 PD-L1 抗体联合治疗诱导的铁死亡辅助光动力免疫治疗导致 T 细胞浸润增加，显著抑制原发性和远处肿瘤生长以及肺转移。
