Expanding the therapeutic window of bacteria for cancer therapy

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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Publication Details

Journal
bioRxiv (Cold Spring Harbor Laboratory)
Published
2026-10-29
DOI
https://doi.org/10.64898/2026.10.27.761579
Primary Topic
Cancer Research and Treatments
Type
preprint

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preprint

Expanding the therapeutic window of bacteria for cancer therapy

Hannah Kim, YoungUk Jang, 진하영, Courtney Coker et al.
2 links
bioRxiv (Cold Spring Harbor Laboratory)
Cancer Research and Treatments
preprint

Expanding the therapeutic window of bacteria for cancer therapy

Hannah Kim, YoungUk Jang, 진하영, Courtney Coker, Jongwon Im, Peter Canoll, Arjun Rohit Adapa, Tal Danino, Kam W. Leong, Jeffrey N. Bruce, Katherine A. Cummins, Xiaoyu Hu, Meghna Komaranchath, Sophia Xi Windemuth, Myra Ashraf, Ronny Drapkin
preprint en

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.

bioRxiv (Cold Spring Harbor Laboratory)
Columbia University Irving Medical Center (US), Columbia University (US), University of Pennsylvania (US)
Herbert Irving Comprehensive Cancer Center, Columbia University, National Science Foundation, Cancer Research Institute, Pershing Square Foundation, Charlie Teo Foundation, National Institutes of Health, National Center for Advancing Translational Sciences
Good health and well-being
Cancer Research and Treatments
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