A bimetallic nanoplatform for STING activation and CRISPR/Cas mediated depletion of the methionine transporter in cancer cells restores anti-tumor immune responses

Abstract

AbstractLack of sufficient cytotoxic T lymphocytes (CD8+ T cells) infiltration and dysfunctional state of CD8+ T cells are considered enormous obstacles to antitumor immunity. Herein, we construct a synergistic nanoplatform to promote CD8+ T cell infiltration in tumors while restoring T cell function by regulating methionine metabolism and activating the STING innate immune pathway. The CRISPR/Cas9 system down-regulates the methionine transporter SLC43A2 and restricts the methionine uptake by tumor cells, thereby relieving the methionine competition pressure of T cells; simultaneously, the released nutrition metal ions activate the cGAS/STING pathway. In this work, the described nanoplatform can enhance the effect of immunotherapy in preclinical cancer models in female mice, enhancing STING pathway mediated immunity and facilitating the development of amino acid metabolic intervention-based cancer therapy.