药理抑制 DPP-4 可促进 CD8(+) T 细胞代谢适应性，从而增强抗肿瘤活性

Metabolic dysfunction is a hallmark of CD8 + T cell exhaustion in the tumor microenvironment.

Thus, there is growing interest in developing strategies that enhance anti-tumor functions of CD8 + T cells via metabolic reprogramming.

Here, we identify dipeptidyl peptidase 4 (DPP-4) as a previously unknown regulator of CD8 + T cell function and metabolism.

We discovered that DPP-4 is upregulated in exhausted CD8 + T cells. Pharmacological inhibition of DPP-4 with the FDA-approved anti-diabetic drug sitagliptin transcriptionally and metabolically reprogrammed CD8 + T cells, increasing spare mitochondrial respiratory capacity, proliferation, cytotoxic mediator production, and antigen-specific cancer cell killing capability.

The functional effects of sitagliptin were dependent on upregulation of glutamate decarboxylase 1 (GAD1), an enzyme that feeds glutamate into the tricarboxylic acid (TCA) cycle, highlighting a new role for GAD1 in CD8 + T cell respiration and proliferation.

We found that systemic inhibition of DPP-4 in preclinical mouse glioblastoma (GBM) models prolongs survival in a CD8 + T cell-dependent manner, and retrospective clinical cohort analysis revealed better outcomes in GBM patients using DPP-4 inhibitors.

Importantly, preconditioning of Chimeric Antigen Receptor (CAR) T-cells with DPP-4 inhibition enhanced their cytotoxicity, persistence, and therapeutic efficacy in pediatric GBM.

Together, our findings provide mechanistic and biological rationale for repurposing readily accessible DPP-4 inhibitors to enhance anti-tumor CD8 + T cell responses.