PTPN2 is encoded by the protein tyrosine phosphatase N2 (also known as TC-PTP) and is a negative regulator of cytokine signaling and macrophage differentiation. In the past decade, our work and others, including several pharmaceuticals, have emphasized that inhibition of PTPN2 and PTPN1 (also known as PTP1B) may act as a new first-of-class cancer immunotherapeutic. Although the potential roles of these two enzymes in various immune cells have been broadly reported, the specific activity of PTPN2 in regulating macrophage immune and metabolic responses has yet to be fully elucidated. Hence, we sought to investigate the function of PTPN2 in macrophage polarization and on their activities. We used two different mouse models to systematically and specifically inhibit the expression of PTPN2 in macrophages and utilized a chemical inhibitor with a macrophage human cell line to assess their immune and metabolic profiles. We demonstrated that PTPN2 ablation in macrophages alters their immunometabolic transcriptome and enhances their proinflammatory response, as observed by increased IFN-É£ and nitric oxide production. PTPN2 deficiency also leads to a dysregulation of mitochondrial respiration, as observed by decreased oxygen consumption and ATP production. We establish herein that PTPN2 dampens the proinflammatory response of macrophages while altering their mitochondrial respiration, validating its macrophage inhibition as a contributing factor in the potency of systemic dual inhibition of PTPN1 and PTPN2 against cancer.