Synapse - Metabolic engineering to facilitate anti-tumor immunity

Metabolic engineering to facilitate anti-tumor immunity Journal Article

Authors:	Schild, T.; Wallisch, P.; Zhao, Y.; Wang, Y. T.; Haughton, L.; Chirayil, R.; Pierpont, K.; Chen, K.; Nunes-Violante, S.; Cross, J.; de Stanchina, E.; Thompson, C. B.; Scheinberg, D. A.; Perry, J. S. A.; Keshari, K. R.
Article Title:	Metabolic engineering to facilitate anti-tumor immunity
Abstract:	Fructose consumption is elevated in western diets, but its impact on anti-tumor immunity is unclear. Fructose is metabolized in the liver and small intestine, where fructose transporters are highly expressed. Most tumors are unable to drive glycolytic flux using fructose, enriching fructose in the tumor microenvironment (TME). Excess fructose in the TME may be utilized by immune cells to enhance effector functions if engineered to express the fructose-specific transporter GLUT5. Here, we show that GLUT5-expressing CD8+ T cells, macrophages, and chimeric antigen receptor (CAR) T cells all demonstrate improved effector functions in glucose-limited conditions in vitro. GLUT5-expressing T cells show high fructolytic activity in vitro and higher anti-tumor efficacy in murine syngeneic and human xenograft models in vivo, especially following fructose supplementation. Together, our data demonstrates that metabolic engineering through GLUT5 enables immune cells to efficiently utilize fructose and boosts anti-tumor immunity in the glucose-limited TME. © 2025 Elsevier Inc.
Keywords:	controlled study; human cell; nonhuman; cd8+ t lymphocyte; t lymphocyte; animal cell; mouse; metabolism; animal experiment; animal model; in vivo study; in vitro study; tumor xenograft; tumor cell; tumor immunity; glucose; macrophage; macrophages; glycolysis; immunocompetent cell; t cell; tumor microenvironment; isograft; carbon source; fructose; metabolic engineering; human; male; female; article; hexose transport; car-t; glucose transporter 5; slc2a5
Journal Title:	Cancer Cell
Volume:	43
Issue:	3
ISSN:	1535-6108
Publisher:	Cell Press
Date Published:	2025-03-10
Start Page:	552
End Page:	562.e9
Language:	English
DOI:	10.1016/j.ccell.2025.02.004
PUBMED:	40020672
PROVIDER:	scopus
PMCID:	PMC11929521
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85219513457&doi=10.1016%2fj.ccell.2025.02.004&partnerID=40&md5=31dfc4fbbbf84bd565bcb9e870a94c75
Notes:	Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Kayvan Keshari -- Source: Scopus