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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, Mohanpur741246, India.

Journal of Medicinal Chemistry
|July 22, 2026
PubMed

Insights

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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