Biosynthesis of Cu 2‐x Se Nanocatalyst Within Probiotics for Repolarization of Tumor Associated Macrophages to Boost Mild Photothermal Sensitized Chemodynamic Immunotherapy

The activation and infiltration of cytotoxic T lymphocytes (CTLs) are the key of tumor immunotherapy. However, the suppressive tumor immune microenvironment usually inhibits the function of CTLs. Tumor-associated macrophages (TAMs) play an important role in remodeling the tumor immune microenvironment. In this work, probiotic Escherichia coli Nissle 1917 (EcN) is used as a bioreactor to achieve intracellular synthesis of copper selenide nanoparticles (Cu_2-xSe NPs), giving Cu_2-xSe@EcN, which effectively repolarize macrophages from pro-tumor M2 phenotype to anti-tumor M1 phenotype mainly through activating MAPK signaling pathway. The synthesized Cu_2-xSe NPs exhibited excellent photothermal performance, inducing hyperthermia-sensitized Fenton-like reaction to catalyze the generation of hydroxyl radical from H₂O₂, then resulted in immunogenic death effect of tumor cells and the repolarization of M2 macrophages. Combined with surface-expressed pathogen-associated molecular patterns (PAMPs) of bacteria, Cu_2-xSe@EcN synergistically promoted DCs maturation and TAMs reprogramming, eventually promoting the infiltration and activation of T cells. Therefore, the bacteria-inorganic hybrid nanomaterials showed satisfied effect in inhibiting tumor growth and recurrence.