Protein tyrosine phosphatase non-receptor type 2 (PTPN2) and protein tyrosine phosphatase non-receptor type 1 (PTPN1) (PTPN2/PTPN1)

Protein tyrosine phosphatase non-receptor type 2 (PTPN2) and type 1 (PTPN1) are closely related enzymes that function as negative regulators of several key signaling pathways, including the JAK-STAT and insulin/leptin pathways [1, 7]. These phosphatases are considered "intracellular checkpoints" because they dephosphorylate signaling proteins that would otherwise promote immune cell activation and tumor cell sensitivity to cytokines [4, 6]. In the context of cancer, dual inhibition of PTPN2 and PTPN1 has been shown to significantly enhance the recruitment and cytotoxic activity of CD8+ T cells and natural killer (NK) cells within the tumor microenvironment [1, 8]. Furthermore, inhibiting these targets makes tumor cells more susceptible to immune-mediated killing by upregulating MHC-I expression and increasing sensitivity to interferon-gamma (IFNγ) [8, 12]. Due to the high sequence homology in their catalytic domains, many therapeutic strategies employ dual inhibitors to prevent functional compensation by one phosphatase when the other is inhibited [10, 11]. Small-molecule inhibitors such as ABBV-CLS-484 are currently in clinical development, representing a first-in-class approach to targeting these previously "undruggable" enzymes for cancer immunotherapy [1, 9]. Beyond oncology, PTPN1 is a well-established target for metabolic diseases like type 2 diabetes and obesity due to its role in insulin resistance [7, 15].

Other names

TC-PTPT-cell protein tyrosine phosphatasePTP1BProtein tyrosine phosphatase 1BPTPN2/1PTPN1/2

Dual inhibition of PTPN2 and PTPN1 catalytic activity, which enhances JAK-STAT signaling, sensitizes tumor cells to interferon-gamma, and promotes the activation and infiltration of CD8+ T cells and natural killer (NK) cells [1, 4, 8].