A dual-cell-targeting epigenetic nano-editor for reshaping the intratumoral T cell niche

T cell-based immunotherapies benefit only a minority of patients, primarily due to insufficient CD8⁺ T cell quantity and functional exhaustion. However, integrated strategies addressing both challenges remain scarce. Epigenetic dysregulation has recently been recognized as an important factor interfering with T cell responses in the tumor microenvironment. Herein, we develop an epigenetic nano-editor (P@cPG/sg) that simultaneously targets the epigenetic lysine-specific demethylase 1 (LSD1) in both tumor cells and T cells to reprogram the intratumoral T cell niche. The nano-editor consists of two guanidinium-based cationic carriers complexed with LSD1-targeting CRISPR/Cas9 plasmids, and can de-crosslink into tumor cell-targeting nanoparticles (P_MG/sg) and T cell-targeting nanoparticles (P_TG/sg). P_MG/sg downregulates LSD1 in tumor cells, leading to the upregulation of chemokines that promote CD8⁺ T cell infiltration. Meanwhile, P_TG/sg reduces LSD1 in T cells, lowering PD-1 expression, significantly enhancing T cell proliferation and rejuvenating exhausted cytotoxic CD8⁺ T cells in situ. Simultaneous LSD1 knockdown establishes a self-reinforcing cascade of anti-tumor immunity, achieving over 75 % tumor growth inhibition in both murine and humanized gastric cancer models. Thus, this nano-editor represents a standalone epigenetic immunotherapy that synchronously enhances intratumoral CD8⁺ T cell quantity and effector function, overcoming key limitations of current T cell-based immunotherapies.