Macrophage-supported metabolic adaptation drives tumor survival under nutrient stress
8 affiliations
- 1Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- 2Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- 3Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- 4Computational Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- 5Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- 6The Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- 7Pat and Ian Cook Doctoral Program in Cancer Engineering, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- 8Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY, USA.
Abstract
Triple-negative breast cancer (TNBC) develops in hypoxic, nutrient-limited tumors enriched with macrophages and cell death. We show that metabolically distinct TNBCs differentially exploit macrophage-derived nutrients, influencing tumor growth and therapeutic response. Prolonged hypoxia reprogrammed mouse and human macrophages, enabling them to release metabolites that rescued the growth of select TNBC cell lines during glutamine deprivation or glutamine metabolism inhibition. Hypoxic macrophages reduced glutamine consumption, increased arginine utilization, and secreted higher levels of ornithine, an intermediate of arginine metabolism. Exogenous ornithine, but not arginine, restored the growth of responsive TNBC cells. Mechanistically, TNBC cells diverted ornithine into proline biosynthesis, supporting oxidative pentose phosphate pathway activity. In vivo, depletion of tumor-associated myeloid cells reduced tumor growth and impaired proline synthesis in glutaminase inhibitor-resistant TNBC. These findings identify hypoxia-driven metabolic cross-talk between macrophages and TNBC cells, revealing ornithine-dependent proline metabolism as a mechanism by which macrophages sustain tumor growth under nutrient stress and contribute to resistance to glutamine-targeted therapies.
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BibTeX
@article{santiappillai2026macrophagesupported,
title = {{Macrophage-supported metabolic adaptation drives tumor survival under nutrient stress}},
author = {Nancy T. Santiappillai and Andrew Cho and Georg Verch and Ana C. Codo and Achuth Nair and Ya-Ting Wang and Allie Lipshutz and Celia Martínez de la Torre and Eric Minwei Liu and Marjan Berishaj and Alissa J. Trzeciak and Zhaoquan Wang and Michelle Saoi and Waleska Saitz Rojas and Justin R. Cross and Ed Reznik and Justin S. A. Perry and Kayvan R. Keshari},
journal = {Science Advances},
year = {2026},
month = oct,
doi = {10.1126/sciadv.aei2831},
url = {https://www.science.org/doi/10.1126/sciadv.aei2831},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Macrophage-supported metabolic adaptation drives tumor survival under nutrient stress
AU - Nancy T. Santiappillai
AU - Andrew Cho
AU - Georg Verch
AU - Ana C. Codo
AU - Achuth Nair
AU - Ya-Ting Wang
AU - Allie Lipshutz
AU - Celia Martínez de la Torre
AU - Eric Minwei Liu
AU - Marjan Berishaj
AU - Alissa J. Trzeciak
AU - Zhaoquan Wang
AU - Michelle Saoi
AU - Waleska Saitz Rojas
AU - Justin R. Cross
AU - Ed Reznik
AU - Justin S. A. Perry
AU - Kayvan R. Keshari
PY - 2026
DA - 2026/10/02
JO - Science Advances
DO - 10.1126/sciadv.aei2831
UR - https://www.science.org/doi/10.1126/sciadv.aei2831
AB - Triple-negative breast cancer (TNBC) develops in hypoxic, nutrient-limited tumors enriched with macrophages and cell death. We show that metabolically distinct TNBCs differentially exploit macrophage-derived nutrients, influencing tumor growth and therapeutic response. Prolonged hypoxia reprogrammed mouse and human macrophages, enabling them to release metabolites that rescued the growth of select TNBC cell lines during glutamine deprivation or glutamine metabolism inhibition. Hypoxic macrophages reduced glutamine consumption, increased arginine utilization, and secreted higher levels of ornithine, an intermediate of arginine metabolism. Exogenous ornithine, but not arginine, restored the growth of responsive TNBC cells. Mechanistically, TNBC cells diverted ornithine into proline biosynthesis, supporting oxidative pentose phosphate pathway activity. In vivo, depletion of tumor-associated myeloid cells reduced tumor growth and impaired proline synthesis in glutaminase inhibitor-resistant TNBC. These findings identify hypoxia-driven metabolic cross-talk between macrophages and TNBC cells, revealing ornithine-dependent proline metabolism as a mechanism by which macrophages sustain tumor growth under nutrient stress and contribute to resistance to glutamine-targeted therapies.
SN - 2375-2548
ER -