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Synergistic Activation of Immunogenic Cell Death and the cGAS-STING Pathway by Engineered Zinc/Manganese-Based

Bingzi Zhu1,2,3, Xiaodong Chen1,2,3, Chang Xu1,2,3

  • 1Department of Colorectal and Anal Surgery, Zhejiang-Finland Joint Laboratory of Gastrointestinal Tumor Metabolism and Nutrition, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|January 28, 2026
PubMed

Insights

Engineered nanoparticles activate the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway and induce immunogenic cell death (ICD) to enhance antitumor immunity. This approach shows promise for colon cancer treatment, especially when combined with immune checkpoint blockade.

Area of Science:

  • Immunology
  • Nanotechnology
  • Cancer Therapy

Background:

  • The cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase-stimulator of interferon genes (cGAS-STING) pathway is vital for anti-tumor immunity.
  • Activating the cGAS-STING pathway alone is often insufficient to eradicate established tumors.
  • Developing strategies to enhance cGAS-STING pathway activation and overcome tumor immunosuppression is critical.

Purpose of the Study:

  • To engineer novel zinc/manganese (Zn/Mn)-based metal-organic framework (MOF) nanoparticles (AMP@Zn/Mn-MOF) for enhanced antitumor immune responses.
  • To investigate the therapeutic potential of AMP@Zn/Mn-MOF in activating the cGAS-STING pathway and inducing immunogenic cell death (ICD).
  • To evaluate the efficacy of AMP@Zn/Mn-MOF in combination with immune checkpoint blockade for colon cancer treatment.

Main Methods:

  • Fabrication of AMP@Zn/Mn-MOF nanoparticles encapsulating the STING agonist c-di-AMP diammonium.
  • Assessment of cGAS-STING pathway activation and innate immune response facilitation by AMP@Zn/Mn-MOF.
  • Evaluation of AMP@Zn/Mn-MOF's peroxidase (POD)-mimetic and glutathione oxidase (GSHox)-mimetic activities.
  • Investigation of AMP@Zn/Mn-MOF's ability to induce immunogenic cell death (ICD) and reprogram the tumor microenvironment.
  • Testing the therapeutic efficacy of AMP@Zn/Mn-MOF in murine MC38 tumor models and in combination with anti-programmed death ligand 1 (αPD-L1) therapy.

Main Results:

  • AMP@Zn/Mn-MOF nanoparticles effectively activated the cGAS-STING pathway and innate immunity.
  • The nanoparticles exhibited POD-mimetic and GSHox-mimetic activities, potentiating tumor cell death and inducing ICD.
  • AMP@Zn/Mn-MOF reprogrammed the immunosuppressive tumor microenvironment by increasing lymphocyte infiltration.
  • Significant suppression of murine MC38 tumor growth was observed with AMP@Zn/Mn-MOF treatment.
  • Combination therapy with AMP@Zn/Mn-MOF and αPD-L1 blockade resulted in amplified antitumor effects and an abscopal effect against distant tumors.

Conclusions:

  • AMP@Zn/Mn-MOF serves as a promising nanoplatform for enhancing antitumor immunity via cGAS-STING pathway activation and ICD induction.
  • This nanoplatform effectively reprograms the tumor microenvironment and synergizes with immune checkpoint blockade.
  • Enhanced immune checkpoint blockade-based immunotherapy using AMP@Zn/Mn-MOF holds significant potential for colon cancer treatment.
Keywords:
Zn/Mn‐MOFcGAS–STING pathwaycolon cancerc‐di‐AMP diammoniumimmunogenic cell death (ICD)

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