蛋白质磷酸酶作为多种重要细胞过程的关键调节因子，是各种疾病的有吸引力的治疗目标。尽管已经花费了大量的精力进行磷酸酶靶向药物的发现，但最初用于竞争性磷酸酶抑制剂的探索饱受药效问题的困扰，导致了磷酸酶被视为难以攻击的目标的污名化。尽管存在困难，但持续的努力已经导致了几种这些酶的药物样、非竞争性调节剂的鉴定，包括SH2结构域含有的蛋白酪氨酸磷酸酶2、蛋白酪氨酸磷酸酶1B、血管内皮蛋白酪氨酸磷酸酶和蛋白磷酸酶1，重新点燃了对磷酸酶治疗靶向性的兴趣。本文讨论了磷酸酶药物发现的最新进展，重点在于开发具有生物活性的选择性调节剂。评估了蛋白质磷酸酶在免疫细胞中的作用和调节，以及它们在免疫肿瘤学和自身免疫性疾病适应症中作为强大目标的潜力。©2023年Springer Nature Limited。

Protein phosphatases act as key regulators of multiple important cellular processes and are attractive therapeutic targets for various diseases. Although extensive effort has been dedicated to phosphatase-targeted drug discovery, early expeditions for competitive phosphatase inhibitors were plagued by druggability issues, leading to the stigmatization of phosphatases as difficult targets. Despite challenges, persistent efforts have led to the identification of several drug-like, non-competitive modulators of some of these enzymes - including SH2 domain-containing protein tyrosine phosphatase 2, protein tyrosine phosphatase 1B, vascular endothelial protein tyrosine phosphatase and protein phosphatase 1 - reigniting interest in therapeutic targeting of phosphatases. Here, we discuss recent progress in phosphatase drug discovery, with emphasis on the development of selective modulators that exhibit biological activity. The roles and regulation of protein phosphatases in immune cells and their potential as powerful targets for immuno-oncology and autoimmunity indications are assessed.© 2023. Springer Nature Limited.