Effect of Ptpn1/2 knockout on the transcriptome of unstimulated or IFN-beta stimulated B16-OVA cells

Here, we identify the phosphatases PTPN1 and PTPN2 as cooperative regulators of tumor immune resistance. Dual genetic ablation or pharmacologic inhibition of PTPN1/2 enhances Type I and II interferon signaling, MHC-I and CXCL9 expression, and sensitizes tumor cells to cytotoxic T lymphocyte–mediated killing.

The small-molecule inhibitor KQ791 phenocopies these effects and synergizes with anti-PD1 therapy to suppress tumor growth in murine models, including immunotherapy-refractory cancers. Mechanistically, PTPN1/2 loss augments STAT1/3/5 signaling and primes cancer cells for immunogenic cell death via IFNγ/TNFα-induced pathways. Moreover, PTPN1/2 inhibition enhances antigen release and cross-presentation, promoting robust antigen-specific CD8⁺ T cell responses.