Expanding the therapeutic window of bacteria for cancer therapy

Im, J.; Komaranchath, M.; Windemuth, S.; Kim, H.; Hu, X.; Adapa, A.; Ashraf, M.; Cummins, K. A.; Coker, C.; Jang, Y.; Jin, H.; Leong, K. W.; Drapkin, R.; Bruce, J. N.; Canoll, P.; Danino, T.

doi:10.64898/2026.10.27.761579

bioRxiv · 10.64898/2026.10.27.761579

Expanding the therapeutic window of bacteria for cancer therapy

Im, J.·Komaranchath, M.·Windemuth, S.·Kim, H.·Hu, X.·Adapa, A.·Ashraf, M.·Cummins, K. A.·Coker, C.·Jang, Y.·Jin, H.·Leong, K. W.·Drapkin, R.·Bruce, J. N.·Canoll, P.·Danino, T.

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Abstract

Engineered bacteria enable self-amplifying therapeutic delivery and immune activation, yet these same features drive systemic toxicity and off-target growth. Here, we create a "tumorobe" that overcomes these limitations by integrating reduced immunogenicity, tumour-restricted growth, and enhanced payload release. Specifically, we identify lipopolysaccharide modifications that reduce immunogenicity while preserving fitness, restrict growth to tumours using a hypoxia-lactate "AND" gate, and enhance extracellular payload release via lipoprotein deletion. This strain expands the maximum tolerated dose in a route-dependent manner by up to 1,000-fold. Across multiple murine models, including colorectal cancer and glioblastoma, the strain drives robust antitumour efficacy as both a standalone therapeutic and an immunotherapeutic delivery platform, achieving durable complete responses in up to 75% of colorectal tumours when armed with a cytokine payload. Together, these results establish a broadly applicable platform for safe and effective bacterial cancer therapy.

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Im, J., Komaranchath, M., Windemuth, S., Kim, H., Hu, X., Adapa, A., Ashraf, M., Cummins, K. A., Coker, C., Jang, Y., Jin, H., Leong, K. W., Drapkin, R., Bruce, J. N., Canoll, P., Danino, T.. 2026-10-29. Expanding the therapeutic window of bacteria for cancer therapy. https://doi.org/10.64898/2026.10.27.761579

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