Science Advances 8(8) (2022) The tumor-suppressor PTPN2 is diminished in a subset of triple-negative breast cancers (TNBCs). Paradoxically, PTPN2-deficiency in tumors or T cells in mice can facilitate T cell recruitment and/or activation to promote antitumor immunity. Here, we explored the therapeutic potential of targeting PTPN2 in tumor cells and T cells. PTPN2-deficiency in TNBC associated with T cell infiltrates and PD-L1 expression, whereas low PTPN2 associated with improved survival. PTPN2 deletion in murine mammary epithelial cells TNBC models, did not promote tumorigenicity but increased STAT-1-dependent T cell recruitment and PD-L1 expression to repress tumor growth and enhance the efficacy of anti-PD-1. Furthermore, the combined deletion of PTPN2 in tumors and T cells facilitated T cell recruitment and activation and further repressed tumor growth or ablated tumors already predominated by exhausted T cells. Thus, PTPN2-targeting in tumors and/or T cells facilitates T cell recruitment and/or alleviates inhibitory constraints on T cells to combat TNBC. American Association for the Advancement of Science PTPN2 elicits cell autonomous and non-cell autonomous effects on antitumor immunity in triple-negative breast cancer CC BY-NC 4.0 International http://creativecommons.org/licenses/by-nc/4.0/ application/pdf doi:10.1126/sciadv.abk3338 https://phaidra.vetmeduni.ac.at/o:1787 eng 2022 Protein-Tyrosine-Phosphatase; Tumor-Infiltrating Lymphocytes; Mediated Gene Deletion; Activation; Promotes; Obesity; Stat1; Expression; Generation; Relevance Goh, Pei Kee (Monash University / Peter MacCallum Cancer Centre) McLean, Catriona (Alfred Hospital) Zeissig, Mara N. (Monash University / Peter MacCallum Cancer Centre) Wiede, Florian (Monash University / Peter MacCallum Cancer Centre) Tiganis, Tony (Monash University / Peter MacCallum Cancer Centre) Humbert, Patrick O. (University of Melbourne / La Trobe University) Müller, Mathias (University of Veterinary Medicine Vienna) Loi, Sherene (Peter MacCallum Cancer Centre / University of Melbourne) Xu, Rachel (Monash University / Peter MacCallum Cancer Centre) Goode, Nathan (La Trobe University) Molloy, Tim (St. Vincent's Centre for Applied Medical Research) Britt, Kara L. (Peter MacCallum Cancer Centre / The University of Melbourne) article