Targeting hematopoietic progenitor kinase 1 (HPK1) for tumor immunotherapy: advances in small molecule inhibitors

Hematopoietic progenitor kinase 1 (HPK1), also known as MAP4K1, is a hematopoietic-specific serine/threonine kinase and a member of the MAP4K family of mammalian Ste20-associated protein kinases, which share a highly similar protein structure, and play important roles in the regulation of cell survival, cell migration, apoptosis and autophagy. HPK1 is a negative regulator of T-cell, B-cell and dendritic cell-mediated immune responses, and HPK1 kinase deficiency increases cytokine secretion and enhances T-cell signaling, viral clearance and tumor growth inhibition. Thus, HPK1 may be implicated in the development and progression of human malignant tumors and is a potent target for anti-tumor immunotherapy. In this review, we summarized the biological rationale and potential of HPK1 as a candidate target for tumor immunotherapy, as well as recent research advances in HPK1 inhibitors, with a special emphasis on HPK1 small molecule inhibitors currently under preclinical and clinical investigation.