Opportunities and challenges for targeting HPK1 in cancer immunotherapy

Hematopoietic Progenitor Kinase 1 (HPK1, also known as MAP4K1) is a hematopoiesis-specific serine/threonine kinase that belongs to the MAP4K family of Ste20-related protein kinases. HPK1 has been identified as a negative regulator of T-cell receptor signaling. Recent studies have indicated that the inhibition or knockout of HPK1 kinase function can effectively alleviate T cell exhaustion, enhance T cell functionality, and improve the therapeutic efficacy of tumor immunotherapy. In recent years, small molecule chemical drugs targeting HPK1 have made significant progress and have become a hot topic in the research and development of tumor immunotherapy drugs. However, the advancement of small molecule drugs that target HPK1 is hindered by various challenges, including the limited selectivity, insufficient immune stimulation, and the ambiguity surrounding role of non-kinase scaffold functions of HPK1 in tumor immune responses. This review briefly describes the biological structure of HPK1 and its related signaling pathways in tumor immunity, systematically discusses the latest research progress in small molecule chemical drugs targeting HPK1. Finally, we summarize and prospect the opportunities and challenges in the drug development of small molecule chemical drugs targeting HPK1 in tumor immunity.