An Immunometabolic Route for Activating cGAS/STING to Drive Anticancer Immunity

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Immunometabolic Circuits in Infection for Advancing Host Directed Therapies
11:12

Immunometabolic Circuits in Infection for Advancing Host Directed Therapies

Published on: September 13, 2024

379

Francisca Borges1, Abhishek D Garg1

  • 1Cell Stress and Immunity (CSI) Laboratory, Department for Cellular and Molecular Medicine (CMM), KU Leuven, Leuven, Belgium.

Cancer Research
|August 15, 2024
PubMed

Insights

Serine deprivation triggers the cGAS/STING pathway, enhancing antitumor immunity. This metabolic strategy shows promise for cancer therapy, boosting immune responses and improving patient survival when combined with PD1 blockade.

Area of Science:

  • Immunology
  • Metabolic pathways
  • Cancer biology

Background:

  • The cGAS/STING pathway is vital for innate immune responses against cancer.
  • Serine, an essential amino acid, impacts tumor growth and immune surveillance.
  • Mitochondrial DNA (mtDNA) release can activate immune signaling pathways.

Purpose of the Study:

  • To investigate the effect of serine deprivation on the cGAS/STING pathway.
  • To explore the potential of serine deprivation as an anticancer therapy.
  • To evaluate the combination of serine deprivation with immune checkpoint inhibitors.

Main Methods:

  • Inducing serine deprivation in cellular and mouse models.
  • Measuring mitochondrial dysfunction and mtDNA release.
  • Assessing immune cell infiltration and type I Interferon (IFN) responses.
  • Analyzing clinical data for serine enrichment signatures in colorectal cancer.

Main Results:

  • Serine deprivation leads to mitochondrial dysfunction and mtDNA release, activating the cGAS/STING pathway.
  • This activation induces type I IFN responses and enhances antitumor immunity, including CD4+/CD8+ T cell infiltration.
  • Lower serine enrichment in colorectal cancer patients correlates with immune activation and better survival.
  • Combining serine deprivation with PD1 blockade significantly reduces tumor volume and establishes long-term immunity in mice.

Conclusions:

  • Serine deprivation is a viable strategy to activate the cGAS/STING pathway and bolster antitumor immunity.
  • This approach enhances the efficacy of immune checkpoint blockade therapies.
  • Serine metabolism modulation offers a promising avenue for improving cancer treatment outcomes.

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