A living enzymatic adenosine switch couples metabolic rescue to IL-12-driven antitumor immunity
Abstract
Cancer cells remodel their metabolic environment to disable infiltrating immune cells. Adenosine is a principal mediator of this immunosuppression, impairing the metabolism and effector functions of T and natural killer (NK) cells. Blocking adenosine receptors or production within a redundant signaling network leaves the metabolite itself intact and has shown limited clinical efficacy. Adenosine deaminase (ADA) instead converts adenosine into inosine, a metabolite that can fuel T cell metabolism. We engineered non-pathogenic, tumor-tropic Escherichia coli K-12 DH5α to surface-display ADA, confining this metabolic switch to the tumor, and co-displayed interleukin-12 (IL-12) to couple metabolic rescue to local immune stimulation. Bacteria-displayed ADA alone restored metabolic and proliferative fitness in adenosine-suppressed lymphocytes to baseline, whereas incorporation of IL-12 coupled this rescue to enhanced effector function. Across multiple preclinical models of hematologic and solid malignancies, the dual-function bacteria were well tolerated, enhanced tumor control, prolonged survival, and induced durable protective immunity against melanoma rechallenge. The bacteria were enriched at tumor sites, reactivated quiescent immune compartments in leukemia, enhanced CAR-NK cell tumor trafficking and activity in pancreatic cancer, and outperformed recombinant proteins in breast cancer. These findings establish a modular living immunotherapeutic strategy that couples a local extracellular metabolic switch with localized cytokine delivery.
Related
- 713 Vitamin B6-mediated lipid metabolic reprogramming as a strategy to restore antitumor T cell immunity in aging
- Deoxysphingolipids activate cGAS-STING and enhance antitumor immunity
- MHCII+ cancer-associated fibroblasts promote antitumor immunity in pancreatic cancer
- 938 A spatially optimized long-acting gp100×CD3×albumin trispecific antibody enables durable antitumor immunity in gp100-expressing solid tumors
- 849 A M2-like tumor-associated macrophage-targeted TLR7/8 agonist, UI-102, induces unique and durable antitumor immunity
BibTeX
@misc{romee2026living,
title = {{A living enzymatic adenosine switch couples metabolic rescue to IL-12-driven antitumor immunity}},
author = {Rizwan Romee and Stephanie Sendker and Shaobo Yang and Eden Bobilev and Alice Chen and Fuguo Liu and Anna Bader and Xingyu Deng and Jenny Ho and Maily Nguyen and Michael James and Veronica Hui and Kate Marinchev and Andreia Maia and Castilleja Albert and Isabella Salinas and Ashley Hu and Alaa Kassim Ali and Jacqueline Garcia and Daniel DeAngelo and Mohammad Rashidian and Bartosz Grzywacz and Robert Soiffer and Jerome Ritz and Catherine Wu and John Koreth and Remy Dulery and Jose Cancelas and Roman Shapiro and Mounica Vallurupalli and Jiahe Li and Andrew Lane and Mubin Tarannum},
howpublished = {Research Square},
year = {2026},
month = oct,
doi = {10.21203/rs.3.rs-11368155/v1},
url = {https://doi.org/10.21203/rs.3.rs-11368155/v1},
note = {CC BY 4.0},
}
RIS
TY - UNPB
TI - A living enzymatic adenosine switch couples metabolic rescue to IL-12-driven antitumor immunity
AU - Rizwan Romee
AU - Stephanie Sendker
AU - Shaobo Yang
AU - Eden Bobilev
AU - Alice Chen
AU - Fuguo Liu
AU - Anna Bader
AU - Xingyu Deng
AU - Jenny Ho
AU - Maily Nguyen
AU - Michael James
AU - Veronica Hui
AU - Kate Marinchev
AU - Andreia Maia
AU - Castilleja Albert
AU - Isabella Salinas
AU - Ashley Hu
AU - Alaa Kassim Ali
AU - Jacqueline Garcia
AU - Daniel DeAngelo
AU - Mohammad Rashidian
AU - Bartosz Grzywacz
AU - Robert Soiffer
AU - Jerome Ritz
AU - Catherine Wu
AU - John Koreth
AU - Remy Dulery
AU - Jose Cancelas
AU - Roman Shapiro
AU - Mounica Vallurupalli
AU - Jiahe Li
AU - Andrew Lane
AU - Mubin Tarannum
PY - 2026
DA - 2026/10/29
PB - Research Square
DO - 10.21203/rs.3.rs-11368155/v1
UR - https://doi.org/10.21203/rs.3.rs-11368155/v1
AB - Cancer cells remodel their metabolic environment to disable infiltrating immune cells. Adenosine is a principal mediator of this immunosuppression, impairing the metabolism and effector functions of T and natural killer (NK) cells. Blocking adenosine receptors or production within a redundant signaling network leaves the metabolite itself intact and has shown limited clinical efficacy. Adenosine deaminase (ADA) instead converts adenosine into inosine, a metabolite that can fuel T cell metabolism. We engineered non-pathogenic, tumor-tropic Escherichia coli K-12 DH5α to surface-display ADA, confining this metabolic switch to the tumor, and co-displayed interleukin-12 (IL-12) to couple metabolic rescue to local immune stimulation. Bacteria-displayed ADA alone restored metabolic and proliferative fitness in adenosine-suppressed lymphocytes to baseline, whereas incorporation of IL-12 coupled this rescue to enhanced effector function. Across multiple preclinical models of hematologic and solid malignancies, the dual-function bacteria were well tolerated, enhanced tumor control, prolonged survival, and induced durable protective immunity against melanoma rechallenge. The bacteria were enriched at tumor sites, reactivated quiescent immune compartments in leukemia, enhanced CAR-NK cell tumor trafficking and activity in pancreatic cancer, and outperformed recombinant proteins in breast cancer. These findings establish a modular living immunotherapeutic strategy that couples a local extracellular metabolic switch with localized cytokine delivery.
SN - 2693-5015
ER -