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The PTPN1 and PTPN2 phosphatases are Cooperative Regulators of Cancer Cell Immune Evasion

Poirier, A.; Walback, E.; Su, R.; Aubry, I.; Wu, C.; St-Laurent, E.; Uttam, S.; Hincapie, A. M.; Colalillo, B.; Hardy, S.; Dore, S.; Tremblay, M. L.

2025-07-05 cancer biology
10.1101/2025.07.02.662801 bioRxiv
Show abstract

Immune evasion by cancer cells remains a major barrier to the success of immune checkpoint blockade (ICB). Here, we identify the phosphatases PTPN1 and PTPN2 as cooperative regulators of tumor immune resistance. Dual genetic ablation of PTPN1/2 in cancer cells 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 IFN{gamma}/TNF-induced pathways. Moreover, PTPN1/2 inhibition enhances antigen release and cross-presentation, promoting robust antigen-specific CD8 T cell responses. These findings highlight PTPN1&2 as essential mediators of cancer immune evasion and support their inhibition as a strategy to broaden the effectiveness of immune checkpoint blockade in solid tumors.

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