An immunomodulatory hydrogel activates dual NF-κB and cGAS-STING pathways to suppress osteosarcoma growth and recurrence

Abstract Osteosarcoma is the most common primary malignant bone tumor in adolescents, significantly impacting their quality of life. The difficulty in removing all residual tumor cells during surgery contributes to the recurrence of osteosarcoma. To provide an alternative strategy, we developed an iron-based polysaccharide hydrogel (gIONPs@CMOT) with immunomodulatory capabilities to activate antitumor immunity and remodel the postoperative tumor immune microenvironment. The hydrogel consisted of oxidized trichosanthes polysaccharide (oTPS), and carboxymethyl chitosan (CMCS), interspersed with glycosaminoglycan-modified Fe3O4 nanoparticles (gIONPs). In vitro and in vivo studies demonstrated that gIONPs in the hydrogel were capable of reprogramming macrophages towards an antitumor phenotype via the nuclear factor-kappa B (NF-κB) pathway. The gIONPs@CMOT hydrogel promoted the maturation of dendritic cells and enhanced their antigen presentation through the cyclic GMP–AMP synthase (cGAS) and stimulator of interferon genes (STING) pathway. The oTPS in the hydrogel not only played a role in crosslinking with CMCS, but also enhanced immune activation. These findings support gIONPs@CMOT as a local immunomodulatory platform for postoperative osteosarcoma by activating antitumor immunity to inhibit tumor growth and suppress tumor recurrence, without significant toxicity.