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Astragalus Polysaccharides Induce Immunogenic Cell Death in Melanoma: A Mechanism Mediated by cGAS/STING Activation
Xi Qiao1, Guiqing Ding1, Qijin Lu1
1Institute of Clinical Immunology, Yue-Yang Hospital of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Abstract:
Astragalus polysaccharides (APS) exhibits potent immunomodulatory properties, yet its interplay with intratumoral microbiota in driving antitumor immunity remains elusive. Herein, we demonstrate that APS suppresses melanoma growth and prolongs survival by inducing immunogenic cell death (ICD) via the cGAS-STING pathway. Inhibition of cGAS-STING abrogated APS efficacy. Notably, depletion of intratumoral microbiota using antibiotics blunted APS-mediated cGAS-STING activation and immune responses, confirming a microbiota-dependent mechanism. 5R 16S rRNA sequencing identified Pseudomonas enrichment as a distinct signature of APS treatment. Crucially, administration of Pseudomonas sterile supernatant was sufficient to activate cGAS-STING signaling, induce ICD, and inhibit tumor growth in microbiota-depleted mice. We propose that APS acts as an upstream modulator that enriches Pseudomonas, creating a microenvironment where bacterial secretions trigger the cGAS-STING pathway to induce ICD. These findings provide a novel theoretical basis for microbiota-targeted immunotherapies.
Insights
Astragalus polysaccharides (APS) enhance antitumor immunity by activating the cGAS-STING pathway, a process dependent on gut bacteria like Pseudomonas, leading to melanoma cell death.
Area of Science:
- Immunology
- Microbiology
- Oncology
Background:
- Astragalus polysaccharides (APS) possess immunomodulatory effects.
- The role of intratumoral microbiota in APS-mediated antitumor immunity is not well understood.
Purpose of the Study:
- To investigate the mechanism by which APS induces antitumor immunity.
- To explore the contribution of intratumoral microbiota in APS efficacy.
Main Methods:
- Melanoma mouse models were treated with APS.
- cGAS-STING pathway activation was assessed.
- Intratumoral microbiota were depleted using antibiotics.
- 16S rRNA sequencing was performed to profile microbial communities.
- Pseudomonas sterile supernatant was administered to microbiota-depleted mice.
Main Results:
- APS suppressed melanoma growth and prolonged survival by inducing immunogenic cell death (ICD) via the cGAS-STING pathway.
- Antibiotic-induced depletion of microbiota abrogated APS efficacy, indicating a microbiota-dependent mechanism.
- APS treatment led to enrichment of Pseudomonas within the tumor microenvironment.
- Administration of Pseudomonas supernatant alone activated cGAS-STING, induced ICD, and inhibited tumor growth in microbiota-depleted mice.
Conclusions:
- APS utilizes the cGAS-STING pathway to induce ICD and exert antitumor effects.
- Intratumoral microbiota, specifically Pseudomonas, are essential for APS-mediated antitumor immunity.
- APS promotes Pseudomonas enrichment, which in turn activates the cGAS-STING pathway, offering a novel therapeutic strategy.
