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bioRxiv · 10.64898/2026.10.04.756258

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

Wang, J.·OuYang, T.·Shi, B.·Meng, H.·Mao, Z.-W.·Xia, W.
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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 (EcN{Delta}pgi-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 ({Delta}pgi) restricts bacterial proliferation to sialic acid-rich tumor microenvironment, significantly enhancing biosafety. In mice, EcN{Delta}pgi-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 EcN{Delta}pgi-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.

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Wang, J., OuYang, T., Shi, B., Meng, H., Mao, Z.-W., Xia, W.. 2026-10-06. Targeted tumor desialylation by engineered probiotic reprograms the tumor microenvironment to potentiate immunotherapy. https://doi.org/10.64898/2026.10.04.756258

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