Lymphoid-tyrosine phosphatase (LYP) is mainly expressed in the immune system and plays an important role in the T-cell receptor (TCR) signaling pathway and tumor immunity. Herein, we identify benzofuran-2-carboxylic acid as a potent pTyr mimic and design a new series of new LYP inhibitors. The most active compound, D34 and D14, reversibly inhibits LYP (K_i = 0.93 μM and 1.34 μM) and possess a certain degree of selectivity toward other phosphatases. Meanwhile, D34 and D14 regulate the TCR signaling by specifically inhibiting LYP. In particular, D34 and D14 significantly suppress tumor growth in an MC38 syngeneic mouse model by boosting antitumor immunity, including activation of T-cell and inhibition of M2 macrophage polarization. Moreover, treatment of D34 or D14 upregulate PD-1/PD-L1 expression, which can be leveraged with PD-1/PD-L1 inhibition to augment immunotherapy. In summary, our study demonstrates the feasibility of targeting LYP for cancer immunotherapy and provides new lead compounds for further drug development.

淋巴酪氨酸磷酸酶（LYP）主要在免疫系统中表达，在T细胞受体（TCR）信号通路和肿瘤免疫中发挥重要作用。在此，我们确定苯并呋喃-2-羧酸是一种有效的 pTyr 模拟物，并设计了一系列新的 LYP 抑制剂。最活跃的化合物D34和D14可可逆地抑制 LYP（K _i  = 0.93 μM 和 1.34 μM），并对其他磷酸酶具有一定程度的选择性。同时，D34和D14通过特异性抑制LYP来调节TCR信号传导。特别是， D34和D14通过增强抗肿瘤免疫（包括激活 T 细胞和抑制 M2 巨噬细胞极化），显着抑制MC38 同基因小鼠模型中的肿瘤生长。此外， D34或D14的治疗会上调 PD-1/PD-L1 表达，这可以与 PD-1/PD-L1 抑制结合使用以增强免疫治疗。总之，我们的研究证明了靶向 LYP 用于癌症免疫治疗的可行性，并为进一步的药物开发提供了新的先导化合物。