Lactate-Depleting Engineered Probiotics Remodel the Tumor Microenvironment and Enhance PD-1 Blockade.

High lactate concentrations in the tumor microenvironment (TME) suppress antitumoral immunity. Although modulating intratumoral lactate is a promising strategy, tumor-targeted interventions remain limited. Here, we developed an engineered probiotic, Lac-EcN, capable of targeted lactate consumption within the TME. Lac-EcN reduces intratumoral lactate levels by over 60% and alleviates tumor acidosis, accompanied by reversal of aberrant NFAT1 nuclear translocation in Tregs and restoration of effector molecule production by cytotoxic T cells. In B16-F10 melanoma and MC-38 colorectal carcinoma models, Lac-EcN combined with anti-PD-1 improves tumor inhibition and extends survival. These results position engineered probiotics as a platform for targeted metabolic intervention in the TME, integrating metabolic reprogramming with immune checkpoint blockade.