Supplement of spermidine enhances anti-tumor immune response

The immune system declines with age, and older people are more susceptible to infections and cancer. PD-1 suppression therapy, which is commonly used compared with younger people, is often ineffective in older people. Studies have shown that spermidine, a biopolyamine present in the body, is decreased with age, and that supplementation with spermidine may improve or delay a number of age-related diseases, including those of the immune system. However, the relationship between spermidine deficiency with aging and age-induced T cell immunosuppression remains unclear.

Recently, Researchers from Kyoto University in Japan published a paper in Science entitled "Spermidine activates mitochondrial trifunctional protein and improves antitumor immunity in mice "research paper. This study revealed that spermidine induces fatty acid oxidation through direct binding and activation of mitochondrial trifunctional protein MTP, which ultimately leads to enhanced mitochondrial metabolism of CD8+ T cells and promotes anti-tumor immunity.

First, the research team verified that the total concentration and intracellular free concentration of spermidine in CD8+T cells of old mice were about half of that of young mice. Therefore, the team examined whether spermidine deficiency was the reason PD-1 did not respond to treatment in aging mice. Spermidine was found to enhance the antitumor activity of PD-1 suppressive immunotherapy in older mice, and spermidine supplementation was also effective in young mice whose tumors did not respond to single anti-PD-1 antibody therapy. The results showed that the combination treatment of spermidine and anti-PD-1 antibody enhanced CD8+T cell proliferation, cytokine production and mitochondrial ATP production, and spermidine effectively enhanced mitochondrial function and significantly improved mitochondrial fatty acid oxidation metabolism within 1 hour.

To explore whether spermidine directly activates fatty acid oxidase (FAO) in mitochondria, the team used biochemical analysis to determine that spermidine binds to mitochondrial trifunctional protein (MTP), the central enzyme of fatty acid beta-oxidation. MTP consists of alpha and beta subunits, both of which bind to spermidine. Experiments using MTP synthesized and purified from Escherichia coli showed that spermidines bind MTP with a strong affinity [binding affinity (dissociation constant, Kd) = 0.1μM] and enhance their enzymatic fatty acid oxidation activity. Specific elimination of the MTP alpha subunit from T cells eliminates the enhanced effect of spermidine on PD-1 suppressor immunotherapy, suggesting that MTP is required for spermidine-dependent T cell activation.

In conclusion, spermidine enhances fatty acid oxidation by directly binding and activating MTP. The supplementation of spermidine can enhance the oxidation activity of fatty acids, improve the mitochondrial activity and cytotoxic function of CD8+T cells. The research team's new understanding of spermidine properties may help develop strategies to prevent and improve the outcomes of age-related immune diseases and combat inresponsiveness to PD-1-suppressing therapies in cancer, regardless of age.