Flagella of Tumor‐Targeting Bacteria Trigger Local Hemorrhage to Reprogram Tumor‐Associated Macrophages for Improved Antitumor Therapy

Abstract Tumor‐associated macrophages (TAMs) exhibit an immunosuppressive M2 phenotype and lead to failure of antitumor therapy. Infiltrated erythrocytes during hemorrhage are recognized as a promising strategy for polarizing TAMs. However, novel materials that precisely induce tumor hemorrhage without affecting normal coagulation still face challenges. Here, tumor‐targeting bacteria (flhDC VNP) are genetically constructed to realize precise tumor hemorrhage. FlhDC VNP colonizes the tumor and overexpresses flagella during proliferation. The flagella promote the expression of tumor necrosis factor α , which induces local tumor hemorrhage. Infiltrated erythrocytes during the hemorrhage temporarily polarize macrophages to the M1 subtype. In the presence of artesunate, this short‐lived polarization is transformed into a sustained polarization because artesunate and heme form a complex that continuously produces reactive oxygen species. Therefore, the flagella of active tumor‐targeting bacteria may open up new strategies for reprogramming TAMs and improving antitumor therapy.