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An Insight into the cGAS-STING Pathway Modulation by Metal Complexes to Initiate Immunogenic Cell Death in Cancer
Shilpendu Ghosh1, Sujato Mukherjee1, Arindam Mukherjee1
1Department of Chemical Sciences and Centre for Advanced Functional Materials (CAFM), Indian Institute of Science Education and Research Kolkata, Mohanpur Campus, Mohanpur 741246, India.
Journal of Medicinal Chemistry
|July 22, 2026
Summary
The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway enhances antitumor immunity. Metal complexes offer novel strategies to activate cGAS-STING signaling, overcoming limitations of current therapies for improved cancer treatment.
Area of Science:
- Immunology
- Oncology
- Materials Science
Background:
- The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is crucial for antitumor immunity, converting "cold" tumors to immune-responsive states.
- Cyclic dinucleotide (CDN) agonists targeting this pathway show clinical promise but face pharmacokinetic and delivery challenges.
- Non-CDN small molecules (e.g., MSA-2, ABZI) and metal complexes offer alternative strategies for cGAS-STING modulation.
Purpose of the Study:
- To explore metal complexes as novel platforms for engaging and amplifying cGAS-STING signaling.
- To investigate the mechanisms by which metal complexes induce immunogenic cell death and enhance antitumor immunity.
- To identify translational challenges and design principles for metal-based cGAS-STING therapeutics.
Main Methods:
- Synthesis and characterization of metal complexes (platinum, ruthenium, iridium, rhodium, gold, copper, manganese, zinc) designed to modulate cGAS-STING.
- Assessment of metal complex-induced nuclear or mitochondrial DNA stress and organelle homeostasis disruption.
- Evaluation of metal complex-mediated immunogenic cell death, including ferroptosis, pyroptosis, and cuproptosis.
Main Results:
- Metal complexes effectively engage cGAS-STING signaling through diverse mechanisms, including redox activity and coordination.
- These complexes induce DNA stress and disrupt organelle function, leading to immunogenic cell death.
- Coupling STING activation with specific cell death modalities (ferroptosis, pyroptosis, cuproptosis) demonstrates therapeutic potential.
Conclusions:
- Metal complexes represent a versatile platform for developing novel cGAS-STING agonists, overcoming limitations of traditional CDN-based therapies.
- Elaborate mechanistic insights are emerging regarding metal complex-induced immune responses and cell death pathways.
- Further research into translational challenges is essential for advancing metal-based immunomodulatory therapeutics.
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