Fig. 1. Mechanisms by which bacteria target tumors.

After systemic administration, bacteria localize to the tumor microenvironment. The interactions between bacteria, cancer cells, and the surrounding microenvironment cause various alterations in tumor-infiltrating immune cells, cytokines, and chemokines, which further facilitate tumor regression. ① Bacterial toxins from S. Typhimurium, Listeria, and Clostridium can kill tumor cells directly by inducing apoptosis or autophagy^{15,24,27–30,41}. Toxins delivered via Salmonella can upregulate Connexin 43 (Cx43), leading to bacteria-induced gap junctions between the tumor and dendritic cells (DCs), which allow cross-presentation of tumor antigens to the DCs^31–33. ② Upon exposure to tumor antigens and interaction with bacterial components, DCs secrete robust amounts of the proinflammatory cytokine IL-1β, which subsequently activates CD8⁺ T cells^21,33. ③ The antitumor response of the activated CD8⁺ T cells is further enhanced by bacterial flagellin (a protein subunit of the bacterial flagellum) via TLR5 activation³⁹. The perforin and granzyme proteins secreted by activated CD8⁺ T cells efficiently kill tumor cells in primary and metastatic tumors^33,41. ④ Flagellin and TLR5 signaling also decreases the abundance of CD4⁺ CD25⁺ regulatory T (T_reg) cells, which subsequently improves the antitumor response of the activated CD8⁺ T cells³⁹. ⑤ S. Typhimurium flagellin stimulates NK cells to produce interferon-γ (IFN-γ), an important cytokine for both innate and adaptive immunity³¹. ⑥ Listeria-infected MDSCs shift into an immune-stimulating phenotype characterized by increased IL-12 production, which further enhances the CD8⁺ T and NK cell responses¹⁴. ⑦ Both S. Typhimurium and Clostridium infection can stimulate significant neutrophil accumulation^8,20,21,44. Elevated secretion of TNF-α^8,21 and TNF-related apoptosis-inducing ligand (TRAIL)⁴⁵ by neutrophils enhances the immune response and kills tumor cells by inducing apoptosis. ⑧ The macrophage inflammasome is activated through contact with bacterial components (LPS and flagellin) and Salmonella-damaged cancer cells, leading to elevated secretion of IL-1β and TNF-α into the tumor microenvironment^21,34. NK cell: natural killer cell. T_reg cell: regulatory T cell. MDSCs: myeloid-derived suppressor cells. P2X₇ receptor: purinoceptor 7-extracellular ATP receptor. LPS: lipopolysaccharide