可控低氧激活的化疗作为增强剂对于癌症光动力免疫疗法的协同作用。
Controllable hypoxia-activated chemotherapy as a dual enhancer for synergistic cancer photodynamic immunotherapy.
发表日期:2023 Jul 26
作者:
Mengyuan Wang, Mengying He, Mengyao Zhang, Shujuan Xue, Tao Xu, Yanan Zhao, Dazhao Li, Feng Zhi, Dawei Ding
来源:
Cell Death & Disease
摘要:
光动力疗法(PDT)的疗效受到肿瘤微环境的缺氧严重制约,而PDT引发的抗肿瘤免疫受到免疫抑制微环境和免疫原性细胞死亡(ICD)缺失的打击。为了同时解决这些关键问题,我们在此创建了一种基于白蛋白的纳米平台,共运载IR780、NLG919二聚体和活性低氧放射疗法合剂tirapazamine(TPZ),作为协同癌症治疗的双重增效剂。在近红外辐射下,IR780产生1O2用于PDT,同时切割ROS敏感连接剂以触发TPZ释放,并通过加剧肿瘤缺氧来激活其化疗作用。同时,我们首次发现,TPZ介导的化疗提高了PDT诱导的肿瘤ICD,引发了包括肿瘤特异性细胞毒性T淋巴细胞(CTL)发育在内的更强的抗肿瘤免疫。最终,富集的肿瘤内GSH触发NLG919的激活,通过特异性indoleamine 2,3-dioxygenase 1(IDO-1)抑制来减轻免疫抑制微环境,从而促进CTL的肿瘤内渗透和原发性及远处肿瘤的杀伤,而形成的记忆T细胞使肿瘤复发和转移近乎100%抑制。这种纳米平台为通过缺氧活化的化疗实现光动力免疫疗法治疗乳腺癌树立了榜样,并为其他缺氧和免疫抑制性恶性肿瘤的治疗铺平了坚实的道路。版权所有©2023。由Elsevier Ltd.出版。
The efficacy of photodynamic therapy (PDT) is severely limited by the hypoxic tumor microenvironment (TME), while the performance of PDT-aroused antitumor immunity is frustrated by the immunosuppressive TME and deficient immunogenic cell death (ICD) induction. To simultaneously tackle these pivotal problems, we herein create an albumin-based nanoplatform co-delivering IR780, NLG919 dimer and a hypoxia-activated prodrug tirapazamine (TPZ) as the dual enhancer for synergistic cancer therapy. Under NIR irradiation, IR780 generates 1O2 for PDT, which simultaneously cleaves the ROS-sensitive linker for triggered TPZ release, and activates its chemotherapy via exacerbated tumor hypoxia. Meanwhile, firstly found by us, TPZ-mediated chemotherapy boosts PDT-induced tumor ICD to evoke stronger antitumor immunity including the development of tumor-specific cytotoxic T lymphocytes (CTLs). Eventually, enriched intratumoral GSH triggers the activation of NLG919 to mitigate the immunosuppressive TME via specific indoleamine 2,3-dioxygenase 1 (IDO-1) inhibition, consequently promoting the intratumoral infiltration of CTLs and the killing of both primary and distant tumors, while the resultant memory T cells allows nearly 100% suppression of tumor recurrence and metastasis. This nanoplatform sets up an example for dully enhanced photodynamic immunotherapy of breast cancer via hypoxia-activated chemotherapy, and paves a solid way for the treatment of other hypoxic and immunosuppressive malignant tumors.Copyright © 2023. Published by Elsevier Ltd.