2. Academic Validation
  3. Disrupting tumor homeostasis with an autoamplificatory nanoinducer to augment pyroptosis for efficient immunotherapy

Disrupting tumor homeostasis with an autoamplificatory nanoinducer to augment pyroptosis for efficient immunotherapy

  • Biomaterials. 2026 Jan:324:123544. doi: 10.1016/j.biomaterials.2025.123544.
Qiaoling Zhang 1,  Ling Lin 1,  Gui Chen 1,  Minyi Nie 1,  Guimei Chen 2,  Yan Tang 2,  Huiyang Chen 1,  Yuanyuan Yang 3,  Zhiqiang Yu 4,  Xing-Jie Liang 5,  Zhenwei Peng 6
Affiliations

Affiliations

  • 1 Department of Laboratory Medicine, Dongguan Key Laboratory of Innovative Molecular Imaging, Dongguan Institute of Clinical Cancer Research, The Tenth Affiliated Hospital (Dongguan People's Hospital), Southern Medical University, Dongguan, 523058, China; Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 2 Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 3 Department of Laboratory Medicine, Dongguan Key Laboratory of Innovative Molecular Imaging, Dongguan Institute of Clinical Cancer Research, The Tenth Affiliated Hospital (Dongguan People's Hospital), Southern Medical University, Dongguan, 523058, China.
  • 4 Department of Laboratory Medicine, Dongguan Key Laboratory of Innovative Molecular Imaging, Dongguan Institute of Clinical Cancer Research, The Tenth Affiliated Hospital (Dongguan People's Hospital), Southern Medical University, Dongguan, 523058, China. Electronic address: yuzq@smu.edu.cn.
  • 5 CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, 100190, China. Electronic address: liangxj@nanoctr.cn.
  • 6 Department of Radiation Oncology, Institute of Precision Medicine, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, China. Electronic address: pzhenw@mail.sysu.edu.cn.
PMID: 40652803 DOI: 10.1016/j.biomaterials.2025.123544
Abstract

Abnormal tumor homeostasis is crucial in maintaining tumor cell survival and growth. Thus, developing effective antitumor strategies that can simultaneously disrupt multiple intracellular homeostatic mechanisms may be more effective and less laborious. Herein, an autoamplificatory nanoinducer (CLRN) composed of Photosensitizer Ce6, glucose metabolism inhibitor lonidamine and methyltransferase inhibitor RG108 is designed and constructed to enhance Pyroptosis and upregulate immunosurveillance by disrupting intracellular redox and metabolic homeostasis. CLRN reduces oxygen consumption by disrupting glucose metabolic homeostasis in hypoxic environments, leading to a massive generation of Reactive Oxygen Species that further disrupt intracellular redox homeostasis. Additionally, CLRN inhibits DNA methylation to upregulate gasdermin E (GSDME) expression, which cooperates with the amplified oxidative stress to activate the Caspase-3/GSDME pathway and activate immunogenic Pyroptosis. As tumor cells undergo immunogenic Pyroptosis, they release various damage-associated molecular patterns and pro-inflammatory cytokines, which promote immune cell infiltration. Furthermore, CLRN reduces lactic acid production by disrupting glucose metabolic homeostasis, thereby reversing the immunosuppressive tumor microenvironment and synergistically eliciting a robust immune response. Ultimately, the developed autoamplificatory nanoinducer effectively suppresses the growth of primary and distant tumors. This facile and feasible design of versatile carrier-free nanoinducer provides an effective approach to trigger immunogenic Pyroptosis and enhance antitumor immunotherapy.

Keywords

Carrier-free nanomedicine; Glucose metabolism; Homeostasis; Pyroptosis; Tumor immunotherapy.

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