斑蝥素锰基鸡尾酒纳米平台共激活铁下垂和STING，用于增强HCC免疫治疗
Cantharidin-manganese based cocktail nanoplatform Co-activating ferroptosis and STING for enhanced HCC immunotherapy.
摘要(中文译文)
肝细胞癌（HCC）常在晚期才被发现，此时治疗选择有限且患者预后普遍较差，因此亟需创新的治疗方法。尽管免疫治疗前景广阔，但其疗效常受到免疫抑制性肿瘤微环境（TME）的限制。为解决这一问题，我们通过简便的“一锅法”开发了一种多功能纳米平台（CTD/MM@BSA），利用牛血清白蛋白（BSA）共同递送化疗药物斑蝥素（CTD）和锰离子（Mn）。该平台利用铁死亡诱导与cGAS-STING通路激活之间的协同相互作用来重塑TME。在被肿瘤细胞内化并随后释放后，CTD和Mn协同作用以提高细胞内ROS水平。这种升高促进了铁死亡和免疫原性细胞死亡（ICD）的诱导。该过程最终导致损伤相关分子模式（DAMPs）的释放，进而激活树突状细胞的成熟。同时，CTD引发的DNA损伤与Mn存在下cGAS对DNA敏感性增强产生协同作用，导致cGAS-STING通路激活显著放大以及随后I型干扰素的产生。这种双向的铁死亡-免疫激活级联反应有效逆转了免疫抑制，促进细胞毒性T细胞应答。它显著抑制了肿瘤生长和转移，同时延长了小鼠的生存期。此外，当与抗PD-L1抗体（aPD-L1）联合使用时，该疗法表现出更强的协同抗肿瘤效果。本研究克服了游离CTD（肝肾毒性）和Mn（肿瘤蓄积差）的局限性，为重塑TME和增强抗肿瘤免疫以治疗HCC提供了一种强效且靶向的策略。
Abstract
Hepatocellular carcinoma (HCC) is often identified during its advanced phases, where therapeutic choices are constrained and patient prognosis is generally poor, creating a critical need for innovative treatment approaches. Despite the promise of immunotherapy, its efficacy is frequently constrained by the immunosuppressive tumor microenvironment (TME). To address this, we developed a multifunctional nanoplatform (CTD/MM@BSA) via a facile "one-pot" method, co-delivering the chemotherapeutic agent cantharidin (CTD) and manganese ions (Mn) using bovine serum albumin (BSA). This platform leverages the synergistic interplay between ferroptosis induction and cGAS-STING pathway activation to remodel the TME. Upon internalization and subsequent release within tumor cells, CTD and Mn act synergistically to boost intracellular ROS levels. This elevation promotes the induction of ferroptosis and ICD. The process culminates in the emission of DAMPs, which in turn activate the maturation of dendritic cells. Simultaneously, DNA damage triggered by CTD acts synergistically with the heightened sensitivity of cGAS to DNA in the presence of Mn, leading to a marked amplification of cGAS-STING pathway activation and the subsequent production of type I interferons. This bidirectional ferroptosis-immunity activation cascade effectively reverses immunosuppression, promoting cytotoxic T-cell responses. It markedly suppresses tumor growth and metastasis while extending the survival of mice. Moreover, when combined with an anti-PD-L1 antibody (aPD-L1), the therapy demonstrates a stronger synergistic anti-tumor effect. This study overcomes the limitations of free CTD (hepatorenal toxicity) and Mn (poor tumor accumulation), offering a potent and targeted strategy to remodel the TME and boost anti-tumor immunity for HCC therapy.
如何引用
AMA
Shengmei Wang, Mengtian Ma, Qiuyan Guo, Guiming Deng, Xinhua Xia, Jianyu Li, et al. Cantharidin-manganese based cocktail nanoplatform Co-activating ferroptosis and STING for enhanced HCC immunotherapy.. Materials today. Bio. 2026; doi:10.1016/j.mtbio.2026.103402.
APA
Shengmei Wang, Mengtian Ma, Qiuyan Guo, Guiming Deng, Xinhua Xia, Jianyu Li, et al (2026). Cantharidin-manganese based cocktail nanoplatform Co-activating ferroptosis and STING for enhanced HCC immunotherapy.. Materials today. Bio. https://doi.org/10.1016/j.mtbio.2026.103402
GB/T 7714
Shengmei Wang, Mengtian Ma, Qiuyan Guo, Guiming Deng, Xinhua Xia, Jianyu Li, et al. Cantharidin-manganese based cocktail nanoplatform Co-activating ferroptosis and STING for enhanced HCC immunotherapy.[J]. Materials today. Bio, 2026 doi:10.1016/j.mtbio.2026.103402.
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