PTPN1 and PTPN2 cooperatively set interferon responsiveness thresholds that govern cancer immune evasion

• 成果类型: Article
• 署名作者: Poirier, Alexandre J.; Feng, Chu-Han; Walback, Erika; Su, Rui; Hincapie, Ana Maria; Aubry, Isabelle; Wu, Chenyue; St-Laurent, Elisabeth; Uttam, Sonali; Colalillo, Bianca; Hardy, Serge; Dore, Samuel; Theberge, Jean-Francois; Tremblay, Michel L.
• 署名单位: McGill University; McGill University; McGill University; McGill University
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2537555123
• 发表日期: 2026-08-18
• 页码: e2537555123
• 关键词: immunotherapy; cancer biology; phosphatases; biochemistry; PROTEIN-TYROSINE-PHOSPHATASE; TC-PTP; 1B; potent; identification; activation; substrate; obesity; kinase; target

摘要

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-mediated 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-refractory 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.