The development of small-molecule inhibitors targeting HPK1

Hematopoietic progenitor kinase 1 (HPK1), a 97-kDa serine/threonine Ste20-related protein kinase, is a negative regulator of T cells, B cells, and dendritic cells-mediated immune responses and is primarily expressed in he-matopoietic lineage cells. HPK1 regulates different cellular processes by interacting with a variety of substrates and adaptors, including immune cell activation, cellular differentiation, proliferation, adhesion, and apoptosis. In HPK1KO mice, T cells over-proliferate in response to stimulation by anti-CD3 and anti-CD28 antibodies, and these cells can secrete more proinflammatory cytokines to enhance T-cell activation and tumor growth inhibition when immunized with T cell-dependent antigens. Therefore, HPK1 may be associated with occurrence and develop-ment of human malignant tumors and is an effective antitumor immunotherapy target. In this perspective review, the biological rationale and potential of HPK1 as a promising candidate target for cancer immunotherapies and the latest research progress of HPK1 are summarized, with special emphasis on the current small-molecule in-hibitors of HPK1 in preclinical and clinical studies.