Abstract / Summary
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.