Ma Yan, Han Mengfan, Zhu Hanchen, Cui Feifei, Qiao Yanqi, Yin Yongmei, Zhao Xiujie, Xi Rimo, Meng Meng
State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and KLMDASR of Tianjin, Nankai University, Tongyan Road, Haihe Education Park, Tianjin 300350, China.
Department of Rehabilitation, Second Hospital of Shandong University, No. 247, Beiyuan Avenue, Jinan 250033, Shandong, China.
Anal Chem. 2025 Jun 17;97(23):12338-12346. doi: 10.1021/acs.analchem.5c01434. Epub 2025 Jun 2.
Recently, immunogenic cell death (ICD) activated by phototherapy has attracted increasing attention in anticancer immunotherapy. Pyroptosis, a lysogenic and inflammatory form of cell death distinct from apoptosis, is considered to enhance the ICD process in tumor cells. Endoplasmic reticulum (ER)-targeted pyroptosis induced by phototherapy is reported to promote the release of inflammatory cytokines and DAMPs and amplify ICD response as a result. However, specific and stable tracking of the ER is more difficult than that of other organelles. In this work, we introduce a dual-modulation strategy to regulate the effect of ERtargeting unit -toluenesulfonamide and twisting conjugation motif on the modification of heptamethine cyanine. A dimer dye (T780T-ER) with twisting structure and four -toluenesulfonamide molecules is ultimately optimized, which can specifically target ER with good stability and efficient Type I PDT capability. Under PDT/PTT stimulation, T780T-ER activates sufficient pyroptosis and causes the release of inflammatory cytokines and DAMPs. , promoted ICD response and strengthened antitumor immunity are confirmed against the growth of primary and distant tumors. Summarily, this study highlights the importance of a multiple-modulation strategy in developing ER-targeted photosensitizers and proposes a Type I PDT molecule (T780T-ER) as an ER stress-dependent pyroptosis inducer to enhance antitumor immunotherapy.
最近，光疗激活的免疫原性细胞死亡（ICD）在抗癌免疫治疗中受到越来越多的关注。焦亡是一种不同于凋亡的溶酶体性和炎症性细胞死亡形式，被认为可增强肿瘤细胞中的ICD过程。据报道，光疗诱导的内质网（ER）靶向焦亡可促进炎性细胞因子和损伤相关分子模式（DAMPs）的释放，并因此放大ICD反应。然而，对内质网进行特异性和稳定的追踪比其他细胞器更困难。在这项工作中，我们引入了一种双重调制策略，以调节内质网靶向单元——对甲苯磺酰胺和扭曲共轭基序对七甲川花菁修饰的影响。最终优化得到了一种具有扭曲结构和四个对甲苯磺酰胺分子的二聚体染料（T780T-ER），其能够以良好的稳定性特异性靶向内质网，并具有高效的I型光动力治疗（PDT）能力。在PDT/光热治疗（PTT）刺激下，T780T-ER激活充分的焦亡，并导致炎性细胞因子和DAMPs的释放。证实其促进了ICD反应，并增强了针对原发性和远处肿瘤生长的抗肿瘤免疫力。总之，本研究强调了多重调制策略在开发内质网靶向光敏剂中的重要性，并提出了一种I型PDT分子（T780T-ER）作为内质网应激依赖性焦亡诱导剂，以增强抗肿瘤免疫治疗。
