The 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.
Abstract
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 H2O2. 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.
BIMLM is developed as a biomimetic nanoplatform integrating lactate oxidase (LOX)-driven lactate exhaustion with MnO2-coated IR-780 for TME remodeling and self-amplifying ROS generation that enhances PDT/CDT efficacy while triggering metabolic starvation and ferroptosis, which collectively enable tumor eradication.
Boye Zhang, Yuli Chen, Pengyan Qiao et al.· Journal of Advanced Research· 0 citations
Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, poses a substantial global health challenge with high mortality and poor therapeutic outcomes, especially in advanced stages. Current therapeutic approaches for HCC, including surgical resection, targeted therapy, immunotherapy, and radiotherapy, are often limited by drug resistance, systemic toxicity, and the complex tumor microenvironment (TME). Herein, we establish the first wool keratin-guided Mn3O4 nanozymes (MnWK) with self-cascade catalytic capability that systematically transforms the TME into a pro-oxidative microenvironment, achieving high therapeutic efficacy through synergistic hypoxia alleviation and ROS-mediated apoptosis. The introduction of WK not only enhances the biocompatibility and colloidal stability of Mn3O4 nanoparticles, but also improves their catalytic performance to enable efficient cascade reactions under physiological conditions. Within the mildly acidic and H2O2-rich TME, MnWK exhibits dual catalase (CAT) and oxidase (OXD)-mimicking activities, driving a well-defined two-step catalytic cascade. Specifically, it first decomposes endogenous H2O2 into O2 to effectively alleviate tumor hypoxia, then converts the in situ generated O2 into cytotoxic superoxide anions. This cascade amplifies oxidative stress and induces selective cancer cell apoptosis via the p38/JNK MAPK signaling pathway. Overall, this work establishes a promising TME-adaptive self-cascade nanotherapeutic system for advancing HCC management.
Hongji Wu, C. Fan, Qikuan He et al.· Small· 0 citations
Combined with anti-PD-1 antibody (α-PD-1), NPMn/Syro exerts synergistic antitumor efficacy, providing a promising therapeutic strategy for clinical management of tumor.
Yanlin Zhou, Ziyi Wu, Tao Zheng et al.· Journal of Controlled Releas...· 0 citations
By integrating receptor-mediated targeting, redox homeostasis disruption, and chemosensitization, MnO2@Man/DOX offers a promising metabolism-oriented strategy for treating refractory TNBC.
Guanghui Mei, Hanwen Wang, Xinhua Lin et al.· Nanomedicine: Nanotechnology...· 0 citations
In vitro and in vivo evaluations confirm that R-A/G@Z effectively suppresses aggressive breast tumors while maintaining a good safety profile, offering a promising strategy for intelligent metabolic-chemodynamic cancer nanomedicine.
Nianting Xiao, Xiao He, Daxiu Li et al.· Journal of Colloid and Inter...· 0 citations
Conventional chemotherapeutic agents are frequently limited by off-target toxicity and suboptimal therapeutic outcomes. Nanomedicines utilizing cell membrane camouflage provide a promising strategy for precise drug delivery and multimodal combination therapy. Herein, we designed a tumor-microenvironment-responsive cell-membrane-coated nanocomposite (designated as ZnO2@MO-D@Mn-CeO2@CM), which consists of a zinc peroxide (ZnO2) core encapsulated within a drug-loaded mesoporous organosilica (MO-D, where D is doxorubicin for the 4T1 breast cancer model and daunorubicin for the C1498 leukemia model) layer, with the mesopores gated by manganese-doped cerium oxide (Mn-CeO2) nanoparticles, and coated with a homologous cell membrane (CM). This nanocomposite enables the release of therapeutic components under acidic conditions and in the presence of elevated glutathione (GSH). It facilitates a combination therapy by integrating chemotherapy, enhanced chemodynamic therapy (CDT), ferroptosis induction, and immunomodulation. Our results demonstrate that this nanocomposite effectively suppresses the progression in 4T1 solid tumor and C1498 leukemia models, demonstrating its potential as a robust combinatorial strategy.
Tong Wang, Yingying Wang, Jianxiang Xu et al.· ACS Applied Materials and In...· 0 citations
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