Antitumor Cytisine-Platinum(IV) Prodrugs Potentiate Crosstalk between Endoplasmic Reticulum and Mitochondria through Calcium Overload Accompanied by Immunogenic Cell Death

Given the critical role of interorganellar communication in cancer malignancy, this study focuses on the regulatory mechanism of calcium signaling mediated by endoplasmic reticulum (ER)-mitochondria contacts in tumor cell apoptosis. A series of Pt(IV) prodrugs derivatives incorporating the natural compound cytisine (CYT) were designed and synthesized, among them, compound CP12 demonstrated significant antitumor activity. CP12 induces ER stress and mediates mitochondrial calcium overload via the IP3R1-GRP75-VDAC1 axis, thereby triggering the collapse of mitochondrial membrane potential, a burst of reactive oxygen species, and ultimately initiating the apoptotic program. Concurrently, CP12 causes dual damage to nuclear and mitochondrial DNA, activates the cGAS-STING pathway, reverses the immunosuppressive tumor microenvironment, and enhances immunogenic cell death (ICD). In vivo, CP12 effectively inhibits lung cancer growth and significantly reduces the characteristic hepatorenal toxicity associated with cisplatin. Through the triple synergistic mechanism of chemical damage, organelle dysfunction, and immune activation, CP12 achieves highly efficient and low-toxicity therapy for lung cancer.