A painless administration of Esketamine combined with Cisplatin (DDP)co‐loaded in a thermo‐sensitive injectable hydrogel (PDEH) is designed to improve the immunosuppressive tumor microenvironment (TME) by activating Dendritic Cells (DCs), interferon‐γ (IFN‐γ) cells and inhibiting regulatory T cells (Tregs) on murine breast cancer. The gene discussed is IFNG; the disease is neoplasm.