Methionine-depleting engineered probiotics promote PD-L1 antibody immunotherapy by activating the STING pathway

The metabolic differences between tumor cells and normal tissue cells offer potential targets for therapeutic intervention. For instance, compared to normal tissues, tumor cells exhibit a significantly higher dependency on methionine. However, current strategies for methionine restriction have limited clinical applicability due to systemic toxicity, poor patient compliance, and insufficient tumor targeting. In this study, we developed an engineered probiotic, Met-EcN, which is able to achieve targeted consumption of methionine within the tumor microenvironment. In the B16-F10 melanoma mouse model, the combination of Met-EcN and anti-PD-L1 antibody led to a 63 % increase in the tumor inhibition rate compared to anti-PD-L1 treatment alone, as well as a 50 % improvement in mouse survival rates. Additionally, this combination significantly enhanced T cell infiltration and activation. In the MC-38 colon cancer model, treatment with Met-EcN alongside anti-PD-L1 antibody inhibited tumor growth by 84.6 %, leading to complete regression of tumors in 80 % of the mice. The depletion of methionine levels by Met-EcN leads to a reduction in methylation levels within tumor cells, which facilitates the dissociation of cGAS protein from chromatin and activates the STING signaling pathway, thereby triggering an innate immune response. This study provides a novel therapeutic approach for overcoming tumor immune resistance.