Synergistic Activation of the STING Pathway via a Mn(II)-Cross-Linked Gel Scaffold To Boost Antitumor Immunotherapy

The development of advanced therapeutic stents to increase anticancer efficiency and bolster antitumor immunity remains a considerable challenge. In this work, a therapeutic gel scaffold made from Mn²⁺-cross-linked sodium alginate (Mn(II)-SA-Gel), which contains a stimulator of interferon genes (STING) agonist (ADU-S100) and an immune checkpoint inhibitor (aCTLA-4), was developed as a drug delivery system for cancer therapy. The gel scaffold preserved its structural integrity and facilitated prolonged drug release via ion coordination exchange with Ca²⁺ present in bodily fluids. In addition to serving as a cross-linking agent during gel formation, Mn²⁺ also facilitates the activation of the STING signaling pathway by ADU-S100, induces dendritic cell maturation, and promotes the polarization of M1 macrophages. Moreover, Mn²⁺ promotes the generation of highly cytotoxic hydroxyl free radicals in the presence of H₂O₂, and in combination with the immune checkpoint inhibitor aCTLA-4, enhances the T-cell immune response to enhance their powerful tumor cell-killing effect. The findings indicated that Mn(II)-SA-Gel could serve as a promising platform to synergistically stimulate the STING pathway, thereby improving cancer immunotherapy.