CD26/DPP4 as a Therapeutic Target in Nonalcoholic Steatohepatitis Associated Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is generally considered an "immune-cold" cancer since T cells are not observed abundantly in HCC tumor tissue. Combination therapy with immune checkpoint inhibitors and vascular endothelial growth factor (VEGF) inhibitors is currently recognized as a first-line systemic treatment for advanced-stage HCC. Immunologically, immune checkpoint inhibitors influence the recognition of cancer cells by T cells, and VEGF inhibitors influence the infiltration of T cells into tumors. However, no drugs that facilitate the trafficking of T cells toward tumors have been developed. Chemokines are promising agents that activate T cell trafficking. On the other hand, metabolic factors such as obesity and insulin resistance are considered risk factors for HCC development. CD26/dipeptidyl peptidase 4 (DPP4) functions as a serine protease, selectively cleaving polypeptides with a proline or alanine at the penultimate N-terminal position, such as chemokines. Recently, CD26/DPP4 has been reported to attenuate anticancer immunity via chemokine cleavage and to promote insulin resistance and inflammation in the liver and/or adipose tissue via dysregulation of macrophage M1/M2 polarization. In this review, we discuss the promotive roles of CD26/DPP4 in HCC development and progression and the potential of DPP4 inhibitors as therapeutic agents for HCC.