Abstract
Cancer immunotherapy benefits only a subset of tumor types, underscoring the need for new targets. The protein tyrosine phosphatases PTPN1 and PTPN2 have emerged as promising candidates and stand out for being amenable to small-molecule inhibition. However, competitive inhibitors inhibit both phosphatases equally, leaving a gap in our understanding of their individual contributions. Herein, we dissected the impact of single and double PTPN1/2 deletion on T cell cytotoxicity. Our results show that while PTPN2 functionally dominates over PTPN1, additional deletion of PTPN1 is required for maximal effect. Transcriptomic profiling revealed that dual deficiency synergistically enhanced the IL-10/STAT3 axis, providing mechanistic insight into their cooperative inhibitory roles. Furthermore, we demonstrate that phosphotyrosine mimetic inhibitors of PTPN1, which were already found to be safe in humans, can be repurposed for cancer immunotherapy. This strategy can be used to increase the efficacy of PD-1 blockade and broaden its use to other cancer types.