PTPN1/PTPN2 inhibition improves NK cancer therapy by enhancing IL-2 and mitigating TGFβ1 responses

Natural killer (NK) cells are promising candidates for allogeneic anti-cancer immunotherapy. However, their cytolytic activity is often suppressed by the tumor microenvironment. We demonstrate that genetic silencing or pharmacological dual inhibition of protein tyrosine phosphatases PTPN1 and PTPN2 (PTPN1/N2) in NK cells significantly enhances anti-tumor cytolytic activity both in vitro and in vivo. This augmented NK cell activity is mediated by increased expression of early activation markers and the production of effector molecules such as granzyme B and interferon-gamma (IFN-γ). Notably, this elevated cell cytolytic response remains substantially resistant to the immunosuppressive effects of TGFβ-1, a cytokine known to dampen NK cell activity and commonly present in the tumor microenvironment. Mechanistically, targeting PTPN1/N2 in NK cells promotes JAK/STAT signaling pathways and sensitizes cells to IL-2 stimulation. Importantly, dual inhibition of PTPN1/N2 markedly enhances the cytolytic activity of cord blood NK cells against patient-derived glioblastoma cells, highlighting the potential of this approach for future therapeutic applications. These findings provide compelling evidence that dual targeting of PTPN1/N2 could significantly improve the efficacy of therapeutic "off-the-shelf" NK cell-based immunotherapy.