AI Article Synopsis
- Cancer immunotherapy, especially PD-1 blockade, is less effective in older adults due to weakened T-cell immunity, which spermidine may help restore by boosting mitochondrial fatty acid oxidation (FAO).
- Researchers developed a spermidine-based probe to identify spermidine-binding proteins and discovered 140 proteins involved, primarily in mitochondria, including key lipid metabolism proteins.
- A synthetic compound named "spermimic" was found to enhance mitochondrial bioenergetics and improve PD-1 therapy in mice, indicating potential for small-molecule cancer treatments that could boost immune responses in patients.
Article Abstract
Cancer immune therapies, particularly programmed cell death protein 1 (PD-1) blockade immunotherapy, falter in aged individuals due to compromised T-cell immunity. Spermidine, a biogenic polyamine that declines along with aging, shows promise in restoring antitumor immunity by enhancing mitochondrial fatty acid oxidation (FAO). Herein, we report a spermidine-based chemoproteomic probe (probe ) that enables profiling of spermidine-binding proteins and screening for small-molecule enhancers of mitochondrial FAO. Chemoproteomic profiling by the probe revealed 140 proteins engaged in cellular interaction with spermidine, with a significant majority being mitochondrial proteins. Hydroxyl coenzyme A (CoA) dehydrogenase subunits α (HADHA) and other lipid metabolism-linked proteins are among the mitochondrial proteins that have attracted considerable interest. Screening spermidine analogs with the probe led to the discovery of compound , which interacts with these lipid metabolism-linked proteins and activates HADHA. This simple and biostable synthetic compound we named "spermimic" mirrors spermidine's ability to enhance mitochondrial bioenergetics and displays similar effectiveness in augmenting PD-1 blockade therapy in mice. This study lays the foundation for developing small-molecule activators of antitumor immunity, offering potential in combination cancer immunotherapy.
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| http://dx.doi.org/10.1021/jacs.3c14615 | DOI Listing |
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Article Synopsis
- Cancer immunotherapy, especially PD-1 blockade, is less effective in older adults due to weakened T-cell immunity, which spermidine may help restore by boosting mitochondrial fatty acid oxidation (FAO).
- Researchers developed a spermidine-based probe to identify spermidine-binding proteins and discovered 140 proteins involved, primarily in mitochondria, including key lipid metabolism proteins.
- A synthetic compound named "spermimic" was found to enhance mitochondrial bioenergetics and improve PD-1 therapy in mice, indicating potential for small-molecule cancer treatments that could boost immune responses in patients.
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