Targeting cGAS-STING pathway offers opportunities for cancer immunotherapy, whereas the clinical performance in treating solid tumors remains unsatisfactory. Emerging evidence indicates that the immunosuppressive tumor microenvironment (TME) severely impedes T cell activation, proliferation and infiltration. The diminished immunogenicity of “cold tumor” complicates the cytotoxicity of T cells, and the rapid metabolism of small-molecule STING agonists accelerates their clearance, thus greatly attenuates the antitumor outcomes. Moreover, the accumulation of endogenous polyamines within tumors considerably suppresses cGAS activity and further weakens the therapeutic efficacy of STING-based immunotherapy. To ad... More
Targeting cGAS-STING pathway offers opportunities for cancer immunotherapy, whereas the clinical performance in treating solid tumors remains unsatisfactory. Emerging evidence indicates that the immunosuppressive tumor microenvironment (TME) severely impedes T cell activation, proliferation and infiltration. The diminished immunogenicity of “cold tumor” complicates the cytotoxicity of T cells, and the rapid metabolism of small-molecule STING agonists accelerates their clearance, thus greatly attenuates the antitumor outcomes. Moreover, the accumulation of endogenous polyamines within tumors considerably suppresses cGAS activity and further weakens the therapeutic efficacy of STING-based immunotherapy. To address these challenges, a supramolecular lipid nanoparticle system (MC7-LNP) has been developed to reprogram the immunosuppressive TME and enhance the therapeutic efficacy of STING agonist. MC7-LNP platform simultaneously incorporates MSA-2 and copper ion through host–guest recognition and metal coordination. A modified cucurbit[7]uril-based lipid facilitates the sustained release of MSA-2 in tumor cells and restricts the function of endogenous polyamines. Concurrently, the oxidative stress induced by copper ion contributes to the formation of damaged DNA and damage-associated molecular patterns, markedly boosting the immunogenicity of tumor cells and revitalizing T cell function. In combination with mRNA encoding the immunostimulatory cytokine IL-12, this innovative supramolecular approach dramatically suppresses melanoma progression and evokes a robust cytotoxic T lymphocytes response. Our findings present a promising synergistic modality to amplify the efficacy of STING agonist-based immunotherapy through TME remodeling.
