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.