Holistic therapeutic philosophy: Boost a cascade communication between endoplasmic reticulum-mitochondria-lysosome to overload intracellular Ca2+ and initiate chemoimmunotherapy

The behaviors of tumor cells relied on the communications between the distinct subcellular organelles through the physical interactions or the released characteristic signals (ions, proteins et al.). Thus, interference with the communications would release the abnormal signals and initiate the improper responses, even the programmed cellular death. Herein, to manipulate the communications between the major suborganelles for the cancer therapy, complex Ru-AM was developed, which could simultaneously accumulate in endoplasmic reticulum (ER), mitochondria (Mito), and lysosome (Lyso). The significant higher rate of mitochondria-associated ER membranes (MAMs) overlay was observed with super-resolution structured illumination microscopy (SIM), resulting in the enhanced Mito-ER contact and Ca2+ release to cytoplasm and Mito. The overloaded mitochondrial Ca2+subsequently evoked the mitophagy with the Mito-Lyso fusion. Moreover, the disruption of intracellular Ca2+ homeostasis was further enhanced with the lysosomal Ca2+ release, due to the lysosomal membrane permeability (LMP), which successfully initiated the immunogenic cell death (ICD). In vivo experiments demonstrated that Ru-AM could effectively inhibit the proliferation of solid tumors and active immune responses. This work not only provided the first metal-based regulator to interfere the intracellular communications between ER-Mito-Lyso, but also demonstrated the effectiveness of the holistic therapeutic philosophy for the cancer chemoimmunotherapy.