A tumor microenvironment-responsive calcium overload nanoplatform inducing PANoptosis for enhanced cancer...

PANoptosis, a newly characterized form of inflammatory programmed cell death that integrates multiple cell death modalities, offers distinct advantages in both potent tumor cell killing and activation of antitumor immunity. However, strategies that can effectively induce PANoptosis in tumor cells remain scarce. Herein, we constructed a tumor microenvironment-responsive nanoplatform (HA-MnO₂-FTY720@CaO₂, HMFC) comprising a CaO₂ core and a MnO₂ shell, loaded with fingolimod (FTY720) and surface-functionalized with hyaluronic acid (HA) for CD44-mediated targeting. Under the mildly acidic and glutathione (GSH)-rich conditions of the tumor microenvironment (TME), the MnO₂ shell degrades, liberating FTY720 and exposing the CaO₂ core. The CaO₂ subsequently decomposes to release Ca²⁺ and H₂O_2. FTY720 inhibits Transient Receptor Potential Melastatin 7 (TRPM7) channels, disrupting Ca²⁺/Mg²⁺ homeostasis and thereby provoking severe calcium overload. Simultaneously, MnO₂ depletes GSH and, together with CaO₂-derived H₂O₂, promotes a Fenton-like reaction that generates abundant reactive oxygen species (ROS), thereby disrupting intracellular redox homeostasis. In addition, Mn²⁺ released from MnO₂ degradation activates the cGAS-STING pathway, further contributing to DC maturation and antitumor immunity. This orchestrated immune response markedly suppresses tumor growth and when combined with anti-PD-L1 therapy, induces a pronounced abscopal effect. Together, our results indicate that calcium overload, FTY720-mediated TRPM7 inhibition, and MnO₂-induced redox imbalance can drive PANoptosis, offering a new concept for enhancing cancer immunotherapy.