Key Laboratory of Luminescence Analysis and Molecular Sensing, Ministry of Education, School of Materials and Energy & Chongqing Engineering Research Center for Micro-Nano Biomedical Materials and Devices, Southwest University, Chongqing, 400715, P. R. China.
The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine, Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, 430079, P. R. China.
Adv Healthc Mater. 2022 Nov;11(21):e2201233. doi: 10.1002/adhm.202201233. Epub 2022 Sep 13.
Cancer immunotherapy is restricted to immune resistance caused by immunosuppressive tumor microenvironment. Pyroptosis involved in antitumor immunotherapy as a new schedule is prospective to reverse immunosuppression. Herein, acidic tumor microenvironment (TME)-evoked MRC nanoparticles (MRC NPs) co-delivering immune agonist RGX-104 and photosensitizer chlorine e6 (Ce6) are reported for pyroptosis-mediated immunotherapy. RGX-104 remodels TME by transcriptional activation of ApoE to regress myeloid-derived suppressor cells' (MDSCs) activity, which neatly creates foreshadowing for intensifying pyroptosis. Considering Ce6-triggered photodynamic therapy (PDT) can strengthen oxidative stress and organelles destruction to increase immunogenicity, immunomodulatory-photodynamic MRC nanodrugs will implement an aforementioned two-pronged strategy to enhance gasdermin E (GSDME)-dependent pyroptosis. RNA-seq analysis of MRC at the cellular level is introduced to first elucidate the intimate relationship between RGX-104 acting on LXR/ApoE axis and pyroptosis, where RGX-104 provides the prerequisite for pyroptosis participating in antitumor therapy. Briefly, MRC with favorable biocompatibility tackles the obstacle of hydrophobic drugs delivery, and becomes a powerful pyroptosis inducer to reinforce immune efficacy. MRC-elicited pyroptosis in combination with anti-PD-1 blockade therapy boosts immune response in solid tumors, successfully arresting invasive metastasis and extending survival based on remarkable antitumor immunity. MRC may initiate a new window for immuno-photo pyroptosis stimulators augmenting pyroptosis-based immunotherapy.
癌症免疫疗法仅限于由免疫抑制性肿瘤微环境引起的免疫抵抗。细胞焦亡参与抗肿瘤免疫治疗作为一种新方案，有望逆转免疫抑制。在此，报告了酸性肿瘤微环境（TME）诱导的 MRC 纳米颗粒（MRC NPs）共递送免疫激动剂 RGX-104 和光敏剂氯 e6（Ce6）用于细胞焦亡介导的免疫治疗。RGX-104 通过转录激活 ApoE 重塑 TME，使髓系来源的抑制细胞（MDSCs）的活性消退，为增强细胞焦亡创造了铺垫。考虑到 Ce6 触发的光动力疗法（PDT）可以增强氧化应激和细胞器破坏以增加免疫原性，免疫调节-光动力 MRC 纳米药物将实施上述双管齐下的策略来增强 GSDME 依赖性细胞焦亡。在细胞水平上对 MRC 进行 RNA-seq 分析，首先阐明了 RGX-104 作用于 LXR/ApoE 轴与细胞焦亡之间的密切关系，其中 RGX-104 为细胞焦亡参与抗肿瘤治疗提供了前提。简而言之，具有良好生物相容性的 MRC 解决了疏水性药物递送的障碍，并成为增强免疫功效的强大细胞焦亡诱导剂。MRC 诱导的细胞焦亡与抗 PD-1 阻断疗法联合使用，可增强实体瘤中的免疫反应，基于显著的抗肿瘤免疫成功阻止侵袭性转移并延长生存。MRC 可能为增强基于细胞焦亡的免疫疗法的免疫-光细胞焦亡刺激剂开辟新窗口。
