{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T16:52:23Z","timestamp":1786467143764,"version":"build-2736575974"},"reference-count":53,"publisher":"National Academy of Sciences","issue":"33","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["FDN-159923"],"award-info":[{"award-number":["FDN-159923"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,8,18]]},"abstract":"<jats:p>Immune evasion by cancer cells remains a major barrier to the success of immune checkpoint blockade (ICB). In recent years, Protein tyrosine phosphatase non-receptor type 2 (PTPN2) has emerged as a promising and druggable target for cancer immunotherapy. Small-molecule agents currently in clinical development to inhibit PTPN2 also exhibit substantial activity against the closely related phosphatase PTPN1. However, the relative contribution of each phosphatase and its direct effect in cancer cells remains unclear. 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\u2013mediated killing. Mechanistically, loss of PTPN1\/2 augments STAT1\/3\/5 signaling, lowering the activation threshold for interferon-driven inflammatory cell death and increasing antigen availability for immune recognition. However, by amplifying STAT1\/3 signaling, PTPN1\/2 ablation or inhibition concomitantly increases PD-L1 expression in tumor cells, thereby revealing the PD-1\/PD-L1 axis as a therapeutic bottleneck during PTPN1\/2 inhibition. Consistent with this model, PTPN1\/2 inhibition sensitized immune checkpoint blockade\u2013refractory tumors to PD-1 blockade in a tumor-intrinsic manner. These findings identify PTPN1\/2 as cooperative mediators of cancer immune evasion and support PTPN1\/2 inhibition as a strategy to enhance the responsiveness of solid tumors to checkpoint blockade.<\/jats:p>","DOI":"10.1073\/pnas.2537555123","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T16:07:56Z","timestamp":1786464476000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["PTPN1 and PTPN2 cooperatively set interferon responsiveness thresholds that govern cancer immune evasion"],"prefix":"10.1073","volume":"123","author":[{"given":"Alexandre J.","family":"Poirier","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01pxwe438","id-type":"ROR","asserted-by":"publisher"}],"name":"Rosalind and Morris Goodman Cancer Institute, McGill University","place":["Montr\u00e9al, 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J. Poirier Proteomics data associated with PTPN1 and PTPN2 cooperatively set interferon responsiveness thresholds that govern cancer immune evasion. PRIDE. https:\/\/doi.org\/10.6019\/PXD064419. Deposited 27 May 2025.","DOI":"10.6019\/PXD064419"},{"key":"e_1_3_4_47_2","unstructured":"A. J. Poirier RNA sequencing data associated with PTPN1 and PTPN2 cooperatively set interferon responsiveness thresholds that govern cancer immune evasion. NCBI Gene Expression Omnibus. https:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE297993. 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