MAP4K1/HPK1

Hematopoietic progenitor kinase 1 (HPK1, also MAP4K1) is a Ste20-related serine/threonine kinase predominantly expressed in hematopoietic cells^[1][2]. HPK1 functions as a negative regulator of T-cell receptor (TCR) signaling by phosphorylating the adaptor protein SLP-76 at Ser376, thereby dampening T-cell activation and cytokine production^[1][2][3]. Mechanistically, HPK1 also suppresses B-cell receptor and dendritic cell signaling, contributing to broad immunomodulatory effects^[1][4][2]. In immune signaling, HPK1 mediates ubiquitination-dependent degradation of downstream targets, including the oncogenic receptor tyrosine kinase AXL in pancreatic cancer cells, linking HPK1 activity to tumor suppressive functions^[5]. Compared with related MAP4K isoforms, such as MAP4K3 (GLK), HPK1 generally inhibits T-cell activation, whereas GLK promotes TCR-mediated signaling and Th17 differentiation^[1][6]. Pharmacological inhibition of HPK1 using small molecules like CompK, BGB-15025, and KHK-6 enhances T-cell activation, cytokine release, and anti-tumor immune responses in preclinical cancer models^[7][8][9]. Structural studies reveal HPK1 exists in multiple conformational states, which underlie its dynamic trans-regulation and inform rational inhibitor design^[10]. High-throughput biochemical and cell-based assays have been developed to quantify HPK1 activity and evaluate inhibitor selectivity and pharmacodynamics, facilitating drug discovery^[3]. Collectively, HPK1 represents a critical checkpoint kinase in immune regulation and a promising target for immuno-oncology interventions^[8][2][4].