<i>N</i>‐Dihydrogalactochitosan Drives Conventional and Alternative Activations of STING to Synergize Type I IFN and IL‐1β Productions for Antitumor Immunity.

N-dihydrogalactochitosan (GC) is an immune stimulant/adjuvant. Synthesized from chitosan and galactose, GC is a new chemical entity that significantly enhances the immune-stimulating properties of its parental material, chitosan, making it a promising therapeutic agent. When used in combination with antigenic material, GC stimulates innate and adaptive antitumor and antiviral immunities. However, its mechanism has not been fully investigated. Herein we demonstrate that GC drives type I IFN activation in antigen-presenting cells (APCs). More importantly, GC drives alternative STING pathways, leading to inflammatory cell death that enhances dendritic cell (DC) activation. GC-activated DCs trigger a variety of nucleic acid sensing pattern recognition receptors (PRRs) pathways and IL-1β production via the activation of the inflammasome. <i>In vivo,</i> GC induces a potent response of type I IFNs and upregulates genes associated with STING signaling within the tumor microenvironment (TME). Moreover, intratumoral delivery of GC reduces the numbers of M2-like macrophages and increases M1-like macrophages residing within the TME, while subsequently increasing the number of activated DCs. Our findings demonstrate that GC acts as a multimodal immune stimulant via STING to generate a broad type I IFN response. This uniquely broad response holds therapeutic promise in generating enhanced antitumor and antiviral immunities.