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. 2025 Mar 10;43(3):552-562.e9.
doi: 10.1016/j.ccell.2025.02.004. Epub 2025 Feb 27.

Metabolic engineering to facilitate anti-tumor immunity

Tanya Schild  1 , Patrick Wallisch  2 , Yixuan Zhao  3 , Ya-Ting Wang  4 , Lyric Haughton  1 , Rachel Chirayil  1 , Kaitlyn Pierpont  2 , Kevin Chen  5 , Sara Nunes-Violante  6 , Justin Cross  6 , Elisa de Stanchina  5 , Craig B Thompson  7 , David A Scheinberg  8 , Justin S A Perry  9 , Kayvan R Keshari  10
Affiliations

Metabolic engineering to facilitate anti-tumor immunity

Tanya Schild et al. Cancer Cell. .

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.

Keywords: CAR-T; fructose; macrophages; metabolic engineering; slc2a5; t cell.

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Conflict of interest statement

Declaration of interests C.B.T. is a founder of Agios Pharmaceuticals. C.B.T. has equity interest in and serves on the Boards of Charles River Laboratories and Regeneron. D.A.S. has equity in, or is a consultant for, or on a Board of: Pfizer, Lilly, Actinium Pharmaceuticals, Arvinas, Eureka Therapeutics, Iovance, Repertoire, and Epics. J.S.A.P. and K.R.K. are founders of Atish Technologies. K.R.K. is a member of the scientific advisory boards of Nvision Imaging Technologies, Imaginostics and Mi2. C.B.T., J.S.A.P., and K.R.K. hold patents related to imaging and modulation of cellular metabolism.

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