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.

doi:10.1101/2025.07.02.662801

bioRxiv · 10.1101/2025.07.02.662801

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.

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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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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. The PTPN1 and PTPN2 phosphatases are Cooperative Regulators of Cancer Cell Immune Evasion. https://doi.org/10.1101/2025.07.02.662801

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