Reprogramming Bacterial Energetics Reverse Lactate-Mediated Immunosuppression for Synergistic Cancer Immunotherapy

Here, we engineered Shewanella oneidensis MR-1 (S. oneidensis) by reprogramming energy metabolism to reverse lactate-driven immunosuppression in the TME. Integration of polyphosphate kinase 2 (PPK2-Ⅰ) and NAD kinase (NADK) markedly augmented bacterial bioenergetics, boosting ATP production by 287.5% and elevating the NADH/NAD⁺ ratio by 299.9% compared to the wild-type strain.

This bioenergetic enhancement accelerated targeted lactate depletion and increased intratumoral bacterial persistence, while impairing tumor lactate transport via downregulation of monocarboxylate transporters MCT1 and MCT4. Crucially, metabolic remodeling reversed immunosuppression by enhancing antigen presentation and CD8+ T cell infiltration, and reducing regulatory T cells (Tregs), thereby converting immunologically “cold” tumors into immunoreactive phenotypes.