Hematopoietic progenitor kinase 1 (MAP4K1) (HPK1)

Hematopoietic progenitor kinase 1 (HPK1), also known as MAP4K1, is a member of the Ste20-like serine/threonine kinase family primarily expressed in hematopoietic cells, including T cells, B cells, and dendritic cells (UniProt P50402). It serves as a critical negative regulator of T-cell receptor (TCR) signaling; upon TCR stimulation, HPK1 phosphorylates the adaptor protein SLP-76 at Ser376, which recruits 14-3-3 proteins and leads to the disassembly of the TCR signalosome, effectively dampening the immune response (PubMed: 20547844). In the context of engineered T cells, such as CAR-T or TCR-T therapies, HPK1 is a major target for genetic ablation or pharmacological inhibition to overcome the immunosuppressive tumor microenvironment. Research indicates that HPK1-deficient T cells exhibit enhanced cytokine production, increased persistence, and superior anti-tumor activity in both solid and hematologic tumor models (PubMed: 32859916). Consequently, HPK1 inhibitors and CRISPR-mediated HPK1-knockout T cells are currently being evaluated in clinical trials to improve the efficacy of adoptive cell therapies and checkpoint blockade strategies.

Other names

MAP4K1Mitogen-activated protein kinase kinase kinase kinase 1MEKKK 1Hematopoietic progenitor kinase 1

Inhibition of kinase activity or genetic deletion to prevent phosphorylation of SLP-76, thereby enhancing T-cell receptor signaling and reducing T-cell exhaustion.