Metformin enhances the anti-tumor effects mediated by attenuated Salmonella typhimurium

[Display omitted] •Metformin enhances St.ΔppGpp-mediated antitumor effects.•Metformin amplifies St.ΔppGpp-mediated immune responses.•Metformin/ St.ΔppGpp increases the protein expression of PEN2, PD1, and PD-L1.•Metformin/ St.ΔppGpp is a promising synergistic strategy to immunotherapy. In bacterial-based cancer therapy, while attenuated Salmonella treatment effectively inhibits tumor progression, single bacterial therapy struggles to completely suppress tumor growth and metastasis. Metformin, a natural compound derived from Galega officinalis L. and known for its antidiabetic properties, also demonstrates significant anti-tumor activity. However, the combined effect of metformin and attenuated Salmonella on tumor treatment has not been thoroughly investigated. In this study, we observed that metformin enhances attenuated Salmonella-mediated recruitment of tumor-infiltrating immune cells, such as NK cells, neutrophils, M1 macrophages, CD4+, and CD8+T lymphocytes in CT26 tumor-bearing mice. Furthermore, the combined treatment of metformin and attenuated Salmonella increases the protein expression of PEN2, PD1, and PD-L1. This finding is likely associated with the enhanced anti-tumor effects of S.t ΔppGpp by metformin, indicating that the combination of S.t ΔppGpp and metformin holds promise as a synergistic strategy for attenuated Salmonella-based immunotherapy.