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July 5th, 2025
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Goodman Cancer Institute, Department of Biochemistry, Department of Microbiology and Immunology, Division of Experimental Medicine, Faculty of Medicine and Heal
cancer biology
biorxiv

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

Poirier, A.Open in Google Scholar•Walback, E.Open in Google Scholar•Su, R.Open in Google Scholar•Aubry, I.Open in Google Scholar•Wu, C.Open in Google Scholar•St-Laurent, E.Open in Google Scholar•Uttam, S.Open in Google Scholar•Hincapie, A. M.Open in Google Scholar•Colalillo, B.Open in Google Scholar•Hardy, S.Open in Google Scholaret al.

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, MHCI 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 IFNg/TNFa 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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