The efficacy of photodynamic therapy (PDT)-related cancer therapies is significantly restricted by two irreconcilable obstacles, i.e., low reactive oxygen species (ROS) generation capability and hypoxia which constrains the immune response. Herein, this work develops a self-assembled clinical photosensitizer indocyanine green (ICG) and the HSP90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) nanoparticles (ISDN) without any excipient. This work discovers that the hydrophobic interaction forces between ICG and 17-DMAG promote the photostability of ICG and its intersystem crossing (ISC) process, thereby improving the ROS quantum yield from 0.112 to 0.46. Augmented ROS generation enhances PDT efficacy and further enhances immunogenic cell death (ICD) effects. 17-DMAG inhibits the HSP90/hypoxia-inducible factor 1α (HIF-1α) axis to dramatically reverse the immunosuppressive tumor microenvironment caused by PDT-aggravated hypoxia. In a mouse model of pancreatic cancer, ISDN markedly improve cytotoxic T lymphocyte infiltration and MHC I and MHC II activation, demonstrating the superior ICD effects in situ tumor and the powerful systematic antitumor immunity generation, eventually achieving vigorous antitumor and recurrence resistance. This study proposes an unsophisticated and versatile strategy to significantly improve PDT efficacy for enhancing systemic antitumor immunity and potentially extending it to multiple cancers.

中文翻译：

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扩大 ROS 生成和缺氧逆转：用于增强癌症光动力免疫治疗的无赋形剂自组装纳米治疗剂


光动力疗法（PDT）相关癌症治疗的疗效受到两个不可调和的障碍的显着限制，即低活性氧（ROS）生成能力和限制免疫反应的缺氧。在此，这项工作开发了一种自组装的临床光敏剂吲哚菁绿（ICG）和HSP90抑制剂17-二甲氨基乙基氨基-17-去甲氧基格尔德霉素（17-DMAG）纳米颗粒（ISDN），无需任何赋形剂。这项工作发现ICG和17-DMAG之间的疏水相互作用力促进了ICG及其系间窜越（ISC）过程的光稳定性，从而将ROS量子产率从0.112提高到0.46。 ROS 生成的增加增强了 PDT 疗效，并进一步增强了免疫原性细胞死亡 (ICD) 效果。 17-DMAG 抑制 HSP90/缺氧诱导因子 1α (HIF-1α) 轴，显着逆转 PDT 加剧缺氧引起的免疫抑制肿瘤微环境。在小鼠胰腺癌模型中，ISDN显着改善细胞毒性T淋巴细胞浸润以及MHC I和MHC II激活，显示出优越的ICD原位肿瘤效应和强大的系统抗肿瘤免疫产生，最终实现强有力的抗肿瘤和抗复发能力。这项研究提出了一种简单且通用的策略，可以显着提高 PDT 疗效，从而增强全身抗肿瘤免疫力，并有可能将其扩展到多种癌症。