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

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-MnO 2 -FTY720@CaO 2 , HMFC) comprising a CaO 2 core and a MnO 2 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 MnO 2 shell degrades, liberating FTY720 and exposing the CaO 2 core. The CaO 2 subsequently decomposes to release Ca 2+ and H 2 O 2. FTY720 inhibits Transient Receptor Potential Melastatin 7 (TRPM7) channels, disrupting Ca 2+ /Mg 2+ homeostasis and thereby provoking severe calcium overload. Simultaneously, MnO 2 depletes GSH and, together with CaO 2 -derived H 2 O 2 , promotes a Fenton-like reaction that generates abundant reactive oxygen species (ROS), thereby disrupting intracellular redox homeostasis. In addition, Mn 2+ released from MnO 2 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 MnO 2 -induced redox imbalance can drive PANoptosis, offering a new concept for enhancing cancer immunotherapy.