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

ABSTRACT: The immunosuppressive tumor microenvironment (TME), driven by lactate accumulation, critically limits cancer immunotherapy efficacy. 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. When combined with 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.

ORGANISM(S): Shewanella oneidensis MR-1

PROVIDER: GSE330449 | GEO | 2026/05/13

REPOSITORIES: GEO

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Project description:Bioelectrochemical systems employing mixed microbial communities as biocatalysts are gaining importance as potential renewable energy, bioremediation, or biosensing devices. While we are beginning to understand how individual microorganism species interact with an electrode as electron donor, not much is known about the interactions between different microbial species in a community. Here, we compare the bioelectrochemical performance of Shewanella oneidensis in a pure-culture and in a co-culture with the homolactic acid fermenter Lactococcus lactis. While S. oneidensis alone can only use lactate as electron donor for current production, the co-culture is able to convert glucose into current with a similar coulombic efficiency of approximately 17%, respectively. With (electro)-chemical analysis and transcription profiling, we found that the BES performance and S. oneidensis physiology were not significantly different whether grown as a pure- or co-culture. These co-culture experiments represent a first step in understanding microbial interactions in BES communities with the goal to design complex microbial communities, which specifically convert target substrates into electricity. Further, for the first time, we elucidated S. oneidensis gene expression with an electrode as the only electron acceptor. The expression pattern confirms many previous studies regarding the enzymatic requirements for electrode respiration, and it generates new hypotheses on the functions of proteins, which are so far not known to be involved in electrode respiration. The BES was either operated with S. oneidensis alone, fed with lactate, or it was operated with S. oneidensis and L. lactis with glucose as primary substrate. The basic medium was a modified M4 medium containing 0.5 g/L yeast extract, 0.5 g/L trypton and 5 g/L glycerol phosphate, besides the commen M4 incredients. S. oneidensis oxidizes lactate to acetate and electrons in a BES - the latter generate a current at a graphite anode. The anode biofilm was harvested after about 4 weeks of continuous BES operation and subjected to total RNA extraction.

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

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