State Key Laboratory of Trauma, Burns and Combined Injury, Institute of Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, China.
School of Medicine, University of Electronic Science and Technology of China, Department of Radiation Oncology, Sichuan Key Laboratory of Radiation Oncology Sichuan Cancer Hospital, Chengdu, 610041, China.
Small. 2022 Aug;18(34):e2202728. doi: 10.1002/smll.202202728. Epub 2022 Jul 7.
Cancer phototherapy activates immunogenic cell death (ICD) and elicits a systemic antitumor immune response, which is an emerging approach for tumor treatment. Most available photosensitizers require a combination of immune adjuvants or checkpoint inhibitors to trigger antitumor immunity because of the immunosuppressive tumor microenvironment and the limited phototherapeutic effect. A class of tumor-targeting heptamethine cyanine photosensitizers modified with an endoplasmic reticulum (ER)-targeting group (benzenesulfonamide) are synthesized. Phototherapy of tumor cells markedly amplifies ER stress and promotes tumor antigen release, as the ER is required for protein synthesis, secretion, and transport. More importantly, different electron-donating or -withdrawing substitutions are introduced into benzenesulfonamide to modulate the nonradiative decay pathways through intramolecular charge transfer, including singlet-triplet intersystem crossing (photodynamic effect) and internal thermal conversion (photothermal effect). Thus, a heptamethine cyanine photosensitizer containing a binitro-substituted benzenesulfonamide (ER-Cy-poNO ) is identified that preferentially accumulates in the ER of tumor cells. It significantly enhances the phototherapeutic effect by inducing excessive ER stress and robust ICD. Consequently, this small molecular photosensitizer triggers a sufficient antitumor immune response and effectively suppresses the growth of both primary and distant metastatic tumors, whereas no apparent toxicity is observed. This heptamethine cyanine photosensitizer has the potential to enhance cancer-targeted immunotherapy.
癌症光疗激活免疫原性细胞死亡（ICD）并引发全身性抗肿瘤免疫反应，这是一种新兴的肿瘤治疗方法。由于免疫抑制性肿瘤微环境和有限的光疗效果，大多数可用的光敏剂需要与免疫佐剂或检查点抑制剂联合使用，以触发抗肿瘤免疫。合成了一类用内质网（ER）靶向基团（苯磺酰胺）修饰的靶向肿瘤的七甲川氰染料光敏剂。肿瘤细胞的光疗显著放大 ER 应激并促进肿瘤抗原释放，因为 ER 是蛋白质合成、分泌和运输所必需的。更重要的是，苯磺酰胺中引入了不同的给电子或吸电子取代基，通过分子内电荷转移来调节非辐射衰减途径，包括单重态-三重态系间窜越（光动力效应）和内部分子热转换（光热效应）。因此，鉴定出一种含有双硝基取代苯磺酰胺的七甲川氰染料光敏剂（ER-Cy-poNO ），它优先聚集在肿瘤细胞的 ER 中。它通过诱导过度的 ER 应激和强烈的 ICD，显著增强了光疗效果。因此，这种小分子光敏剂引发了足够的抗肿瘤免疫反应，并有效地抑制了原发性和远处转移性肿瘤的生长，而没有观察到明显的毒性。这种七甲川氰染料光敏剂有可能增强癌症靶向免疫治疗。
