Abstract：
Zinc homeostatic medicine is of great potential for cancer chemo-immunotherapy; however, there are few reports on antitumor compounds that can trigger Zn2+ -mediated immune responses. In this work, we developed a novel cyclometalated PtIV -terthiophene complex, Pt3, that not only induces DNA damage and cellular metabolism dysregulation, but also disrupts zinc homeostasis as indicated by the abnormal transcriptional level of zinc regulatory proteins, excess accumulation of Zn2+ in cytoplasm, and down-regulation of metallothioneins (MTs), which further caused redox imbalance. The simultaneous disruption of zinc and redox homeostasis in response to Pt3 treatment activated gasdermin-D mediated pyroptosis accompanied by cytoskeleton remodeling, thus releasing pro-inflammatory cytokines to promote dendritic cell (DC) maturation and T cell tumor-infiltration, eventually eliminating both primary and distant tumors in vivo. As far as we know, this is the first metal complex that can regulate zinc homeostasis to activate antitumor immunity.
摘要：
锌稳态药物在癌症化学免疫疗法中具有巨大潜力，然而,关于能引发Zn2+介导的免疫反应的抗肿瘤化合物的报道很少。在这项工作中,我们开发了一种新型的环金属化Pt(IV)-叔噻吩复合物Pt3，不仅诱导DNA损伤和细胞代谢失调，但也破坏锌稳态，如锌调节蛋白的异常转录水平所表明，细胞质中Zn2+的过量积累，和金属硫蛋白（MTs）的下调，这进一步导致了氧化还原失衡。响应Pt3治疗的锌和氧化还原稳态的同时破坏激活gasdermin-D介导的焦亡伴随细胞骨架重塑，从而释放促炎细胞因子以促进树突状细胞（DC）成熟和T细胞肿瘤浸润，最终在体内消除原发性和远处肿瘤。据我们所知,这是第一个可以调节锌稳态以激活抗肿瘤免疫的金属络合物。
