Triple-pathway cGAS-STING activation collaborated with ferroptosis-induced immunogenic cell death for boosting systemic colorectal cancer immunotherapy

Immunotherapy for advanced colorectal cancer has made the considerable progress. However, the most patients have unsatisfactory immune response due to immunosuppressive tumor microenvironment (TME). We construct a hyaluronic acid (HA) functionalized nanoplatform (MnOx@MIL-100@CDDP@HA, MMCH) with MnOx as core and MIL-100 as shell for loading cisplatin to boost the antitumor immune response by the synergistic effect of activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway and ferroptosis-induced immunogenic cell death. MMCH could achieve the TME-responsive CDDP release and alleviating tumor hypoxia, which effectively increased the damage of nuclear DNA (nDNA) to improve the efficacy of chemotherapy. The abilities of consuming GSH and producing ·OH of MMCH could cause ferroptosis, further induced immunogenic cell death (ICD), result in boosting an adaptive immune response. The generated ROS and CDDP caused damage to nDNA and mitochondrial DNA (mitoDNA), and further initiated the cGAS-STING pathway to trigger innate immune, which could be enhanced by Mn²⁺ via improving sensitivity of cGAS to dsDNA. The activation of adaptive and innate immune response could result in an excellent antitumor immunity response and long-lasting immunological memory, remarkably impede primary tumor growth and relapse in vitro and vivo. Therefore, this strategy of provoking cGAS-STING pathway and inducing ferroptosis has a promising potential to induce adaptive and innate immune response for boosting colorectal cancer immunotherapy.