Acetyl-CoA Carboxylase Obstructs CD8+ T-Cell Lipid Utilization and Energy Synthesis in the Tumor Microenvironment
Hunt, E. G.; Hurst, K. E.; Riesenberg, B. P.; Kennedy, A. S.; Gandy, E. J.; Andrews, A. M.; Wallace, E. D.; Gao, P.; Coleman, M.; Thaxton, J. E.
Show abstract
The solid tumor microenvironment (TME) imprints a compromised metabolic state in tumor infiltrating T cells (TILs) hallmarked by the inability to maintain effective energy synthesis for antitumor function and survival. T cells in the TME must catabolize lipids via mitochondrial fatty acid oxidation (FAO) to supply energy in nutrient stress, and it is established that T cells enriched in FAO are adept at cancer control. However, endogenous TILs and unmodified cellular therapy products fail to sustain bioenergetics in tumors. Using patient samples and mouse models, we reveal that the solid TME imposes perpetual acetyl-CoA carboxylase (ACC) activity, enforcing lipid biogenesis and storage in TILs that directly opposes FAO. Using metabolic, lipidomic, and confocal imaging strategies, we find that restricting ACC wholly rewires T cell metabolism, enabling energy maintenance in TME stress. Moreover, limiting ACC activity potentiates a gene and phenotypic program indicative of T cell memory, engendering TILs with increased survival and polyfunctionality, with the ability to control solid cancer.
Matching journals
The top 5 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Bmal1 integrates mitochondrial metabolism and macrophage activation 96%
- Oxygen levels at the time of activation determine T cell persistence and immunotherapeutic efficacy 95%
- Multi-omic Characterization of Pancreatic Cancer-Associated Macrophage Polarization Reveals Deregulated Metabolic Programs Driven by the GMCSF-PI3K Pathway 95%
Similar papers in this journal
Similar papers in this journal
- Targeting de novo lipogenesis and the Lands cycle induces ferroptosis in KRAS-mutant lung cancer 96%
- CDK4 inactivation balances resistance to apoptosis with heightened metabolic sensitivity in triple negative breast cancer cells 95%
- Metformin enhances anti-mycobacterial responses by educating immunometabolic circuits of CD8+ T cells 95%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.