Reprogramming bacterial energetics reverses lactate-mediated immunosuppression for synergistic cancer immunotherapy.

The immunosuppressive tumor microenvironment (TME), driven by lactate accumulation, critically limits cancer immunotherapy efficacy. In this research article, we engineered Shewanella oneidensis (S. oneidensis) MR-1 by reprogramming energy metabolism to reverse lactate-driven immunosuppression in the TME. Integration of polyphosphate kinase 2 and NAD kinase markedly augmented bacterial bioenergetics, boosting ATP production by 287.5% and elevating the NADH/NAD+ ratio by 299.9% compared with the 'wild-type' (WT) 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, thereby converting immunologically 'cold' tumors into immunoreactive phenotypes. When combined with anti-programmed cell death protein 1 (αPD-1) immunotherapy, this strategy synergistically amplified antitumor efficacy and established durable immunological memory against recurrence. Collectively, our work establishes a paradigm for bacterial bioenergetic engineering to advance cancer immunotherapy.