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  3. Targeting ROS-metabolism dual pathways to trigger PANoptosis by cobalt-vanadium oxides biomimetic nanocakes for tumor immunotherapy

Targeting ROS-metabolism dual pathways to trigger PANoptosis by cobalt-vanadium oxides biomimetic nanocakes for tumor immunotherapy

  • Biomaterials. 2025 Sep 17:326:123726. doi: 10.1016/j.biomaterials.2025.123726.
Silin Du 1,  Guangyu Ma 2,  Xiang Li 3,  Minghao Chao 4,  Liying Fan 1,  Zhiqiang Zhao 2,  Rongze Tang 2,  Junjie Li 2,  Chaonan Jing 2,  Yufan Liu 2,  Dehong Yu 5,  Zhao Liu 6,  Fenglei Gao 7
Affiliations

Affiliations

  • 1 Department of Thyroid and Breast Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China; Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China.
  • 2 Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China.
  • 3 Department of Orthopedics, The Affiliated Huai'an Hospital of Xuzhou Medical University, The Second People's Hospital of Huai'an, Huai'an, 223002, China.
  • 4 Department of Orthopaedic Surgery, Lishui Central Hospital and Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, 323000, Zhejiang Province, China.
  • 5 Department of Oncology, The Affiliated Pizhou Hospital of Xuzhou Medical University, Pizhou, Jiangsu, 221399, China. Electronic address: 15380117222@163.com.
  • 6 Department of Thyroid and Breast Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China; Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China. Electronic address: xylzhao9999@163.com.
  • 7 Department of Thyroid and Breast Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, China; Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China; Department of Oncology, The Affiliated Pizhou Hospital of Xuzhou Medical University, Pizhou, Jiangsu, 221399, China. Electronic address: flgao@xzhmu.edu.cn.
PMID: 40987137 DOI: 10.1016/j.biomaterials.2025.123726
Abstract

To overcome the resistance of tumor cells to death through a single pathway, PANoptosis, a novel synergistic mode of cell death, can simultaneously activates Pyroptosis, Apoptosis, and Necroptosis. Most current strategies for inducing PANoptosis focused on amplifying Reactive Oxygen Species (ROS) through exogenous stimuli, while the regulatory role of tumor cell metabolic characteristic in this process has long been overlooked. We propose a ROS-Metabolism dual axis synergistic induction of PANoptosis, simultaneously enhancing antitumor immune responses, and construct a novel bionic nanoplatform named CVOVM. This platform consists of CoVOx nanocakes and the glutamine transporter inhibitor V-9302, with 4T1 cell membranes as camouflage. In tumors, CVOVM initiates a series of catalytic reactions: CoVOx promotes numerous ROS generation, while V-9302 disrupts glutamine metabolism, depleting glutathione (GSH) and nicotinamide adenine dinucleotide (NAD+), thereby triggering the assembly of PANoptosome primarily composed of NLRP3 and NLRC5, which initiates Pyroptosis, Apoptosis, and Necroptosis. The occurrence of PANoptosis promotes immunogenic cell death (ICD) to remodel tumor immunosuppressive microenvironment, and enhances immunotherapy and inhibits lung metastasis. Overall, we present a previously unreported mechanis to achieve the synergistic induction of PANoptosis through ROS amplification and metabolic inhibition, enhancing antitumor immunity, and potentially providing new opportunities and possibilities for combination Cancer therapy.

Keywords

Cobalt; Glutamine metabolism; Immunotherapy; PANoptosis; Vanadium.

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