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

ABSTRACT 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‐x Se NPs), giving Cu 2‐x Se@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‐x Se NPs exhibited excellent photothermal performance, inducing hyperthermia‐sensitized Fenton‐like reaction to catalyze the generation of hydroxyl radical from H 2 O 2 , 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‐x Se@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.