Targeted tumor desialylation by engineered probiotic reprograms the tumor microenvironment to potentiate immunotherapy

Abstract

Tumor hypersialylation drives immunosuppression and limits immunotherapy efficacy by shielding tumor cells and engaging inhibitory immune receptors. Here, we engineered Escherichia coli Nissle 1917 (EcNΔpgi-SAS) as a metabolically confined “desialylation catalyst” to remodel the tumor microenvironment. This strain combines HER2-directed adhesion, hypoxia-inducible surface sialidase display for targeted glycan cleavage, and sialic acid catabolism to prevent glycolytic recycling. Critically, disrupting glucose metabolism (Δpgi) restricts bacterial proliferation to sialic acid-rich tumor microenvironment, significantly enhancing biosafety. In mice, EcNΔpgi-SAS colonized tumors and effectively desialylated tumor cells, synergizing with anti-PD-L1 to suppress growth of immunologically “cold” tumors. Mechanistically, desialylation reversed immunosuppression by broadly enhancing antitumor immunity. Orally administered EcNΔpgi-SAS substantially inhibited colorectal carcinogenesis, repaired epithelial barrier integrity by restoring tight junctions, and prevented adenoma formation. This integrated strategy establishes a clinically translatable platform for reversing immunosuppression in solid tumors.