Astragalus Polysaccharides Induce Immunogenic Cell Death in Melanoma: A Mechanism Mediated by cGAS/STING Activation via Intratumoral Microbiota Modulation.

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.