The inhibition of protein tyrosine phosphatases 1B (PTP1B) and N2 (PTPN2) has emerged as an exciting approach for bolstering T cell anti-tumor immunity. ABBV-CLS-484 is a PTP1B/PTPN2 inhibitor in clinical trials for solid tumors. Here we have explored the therapeutic potential of a related small-molecule-inhibitor, Compound-182. We demonstrate that Compound-182 is a highly potent and selective active site competitive inhibitor of PTP1B and PTPN2 that enhances T cell recruitment and activation and represses the growth of tumors in mice, without promoting overt immune-related toxicities. The enhanced anti-tumor immunity in immunogenic tumors can be ascribed to the inhibition of PTP1B/PTPN2 in T cells, whereas in cold tumors, Compound-182 elicited direct effects on both tumor cells and T cells. Importantly, treatment with Compound-182 rendered otherwise resistant tumors sensitive to α-PD-1 therapy. Our findings establish the potential for small molecule inhibitors of PTP1B and PTPN2 to enhance anti-tumor immunity and combat cancer.

抑制蛋白酪氨酸磷酸酶 1B (PTP1B) 和 N2 (PTPN2) 已成为增强 T 细胞抗肿瘤免疫的一种令人兴奋的方法。ABBV-CLS-484 是一种 PTP1B/PTPN2 抑制剂，正在进行实体瘤临床试验。在这里，我们探索了相关小分子抑制剂，Compound-182 的治疗潜力。我们证明，Compound-182 是一种高效、选择性的 PTP1B 和 PTPN2 活性位点竞争性抑制剂，可增强 T 细胞的募集和激活并抑制小鼠肿瘤的生长，而不会促进明显的免疫相关毒性。免疫原性肿瘤中抗肿瘤免疫力的增强可归因于 T 细胞中 PTP1B/PTPN2 的抑制，而在冷肿瘤中，Compound-182 对肿瘤细胞和 T 细胞均产生直接作用。重要的是，使用化合物 182 治疗可使原本耐药的肿瘤对 α-PD-1 疗法敏感。我们的研究结果证实了 PTP1B 和 PTPN2 小分子抑制剂增强抗肿瘤免疫力和对抗癌症的潜力。