Immune checkpoint blockade is effective for some patients with cancer, but most are refractory to current immunotherapies and new approaches are needed to overcome resistance^1,2. The protein tyrosine phosphatases PTPN2 and PTPN1 are central regulators of inflammation, and their genetic deletion in either tumour cells or immune cells promotes anti-tumour immunity^3,4,5,6. However, phosphatases are challenging drug targets; in particular, the active site has been considered undruggable. Here we present the discovery and characterization of ABBV-CLS-484 (AC484), a first-in-class, orally bioavailable, potent PTPN2 and PTPN1 active-site inhibitor. AC484 treatment in vitro amplifies the response to interferon and promotes the activation and function of several immune cell subsets. In mouse models of cancer resistant to PD-1 blockade, AC484 monotherapy generates potent anti-tumour immunity. We show that AC484 inflames the tumour microenvironment and promotes natural killer cell and CD8⁺ T cell function by enhancing JAK–STAT signalling and reducing T cell dysfunction. Inhibitors of PTPN2 and PTPN1 offer a promising new strategy for cancer immunotherapy and are currently being evaluated in patients with advanced solid tumours (ClinicalTrials.gov identifier NCT04777994). More broadly, our study shows that small-molecule inhibitors of key intracellular immune regulators can achieve efficacy comparable to or exceeding that of antibody-based immune checkpoint blockade in preclinical models. Finally, to our knowledge, AC484 represents the first active-site phosphatase inhibitor to enter clinical evaluation for cancer immunotherapy and may pave the way for additional therapeutics that target this important class of enzymes.

免疫检查点阻断对一些癌症患者有效，但大多数对当前的免疫疗法无效，需要新的方法来克服耐药^{性 1,2}。蛋白酪氨酸磷酸酶 PTPN2 和 PTPN1 是炎症的中枢调节因子，它们在肿瘤细胞或免疫细胞中的基因缺失可促进抗肿瘤免疫^3,4,5,6。然而，磷酸酶是具有挑战性的药物靶点;特别是，活性位点被认为不可成药。在这里，我们介绍了 ABBV-CLS-484 （AC484） 的发现和表征，这是一种一流的、口服生物可利用的、有效的 PTPN2 和 PTPN1 活性位点抑制剂。体外 AC484 治疗放大对干扰素的反应并促进几种免疫细胞亚群的激活和功能。在对 PD-1 阻断耐药的癌症小鼠模型中，AC484 单一疗法产生有效的抗肿瘤免疫力。我们表明 AC484 通过增强 JAK-STAT 信号传导和减少 T 细胞功能障碍来发炎肿瘤微环境并促进自然杀伤细胞和 CD8⁺ T 细胞功能。PTPN2 和 PTPN1 抑制剂为癌症免疫治疗提供了一种有前途的新策略，目前正在晚期实体瘤患者 （ClinicalTrials.gov 标识符 NCT04777994） 中进行评估。更广泛地说，我们的研究表明，关键细胞内免疫调节因子的小分子抑制剂可以达到与临床前模型中基于抗体的免疫检查点阻断相当或超过的疗效。最后，据我们所知，AC484 是第一个进入癌症免疫治疗临床评估的活性位点磷酸酶抑制剂，可能为针对这类重要酶的其他疗法铺平道路。