Spermidine activates mitochondrial trifunctional protein and improves antitumor immunity in mice

Spermidine (SPD) delays age-related pathologies in various organisms. SPD supplementation overcame the impaired immunotherapy against tumors in aged mice by increasing mitochondrial function and activating CD8 + T cells. Treatment of naïve CD8 + T cells with SPD acutely enhanced fatty acid oxidation. SPD conjugated to beads bound to the mitochondrial trifunctional protein (MTP). In the MTP complex, synthesized and purified from Escherichia coli , SPD bound to the α and β subunits of MTP with strong affinity and allosterically enhanced their enzymatic activities. T cell–specific deletion of the MTP α subunit abolished enhancement of programmed cell death protein 1 (PD-1) blockade immunotherapy by SPD, indicating that MTP is required for SPD-dependent T cell activation. Abundance of the polyamine spermidine decreases in aging mice, and supplementation can have restorative effects and extend life span. Al-Habsi et al . explored whether loss of spermidine might contribute to loss of antitumor immunity in aged mice. Restoration of spermidine concentrations enhanced antitumor responses stimulated by programmed death ligand-1 (PD-L1) monoclonal antibody therapy. Spermidine appeared to directly affect T cell function by increasing fatty acid oxidation. Tagged spermidine bound to components of the mitochondrial trifunctional protein complex, thus increasing fatty acid oxidation and the production of ATP. The authors propose that these effects may contribute to the effects of spermidine in promoting longevity. —LBR Spermidine helps to restore antitumor immunity in older mice.