Nanomessenger-Mediated Signal Crosstalk Encodes Multithreading Death Program Against Tumor Metastasis.

The regulation of death programs is central to malignant behaviors and immune evasion of tumor cells and represents a promising therapeutic target in cancer therapy. The main challenge lies in how to utilize associated signaling among different cell death processes for amplifying antitumor effect. This study proposes an effective "signal crosstalk" strategy driven by the disruption of intracellular messenger homeostasis, which triggers concurrent death pathways and immune activation to suppress metastasis. The CaS@ZIF-8 nanomessengers are engineered to augment intracellular Ca2+, Zn2+, and H2S concentrations. Through molecular interlink of the downstream signaling network, a "necroptosis-anoikis-apoptosis" crosstalk pattern is elicited to realize efficient immunogenic cell death (ICD) effect. The sufficient ICD effect reverses the immunosuppressive microenvironment to facilitate antigen presentation and the intratumoral infiltration of immune cells. Furthermore, the crosstalk pattern effectively downregulates adhesion- and metastasis-associated factors to prevent tumor cells re-implantation. The strategy thereby fosters adaptive antitumor immunity and reinstates immune surveillance against tumor metastasis. Our findings elucidate the mechanism of nanomessenger-mediated multithreading death program and provide a crucial basis for targeted intervention of cell death patterns to treat diseases.