{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTNFAIP8L2 (TIPE2) is a critical immune‐negative regulator that helps maintain immune homeostasis. It is preferentially expressed in lymphoid tissues – for instance, in T cells and macrophage‐derived cells – and its reduced expression has been linked to exaggerated inflammatory responses. Low levels of TIPE2 are observed in patients with chronic hepatitis B, in cases of mycoplasma pneumonia, and in certain kidney transplant rejection scenarios, where diminished TIPE2 correlates with elevated cytokine production and enhanced cytotoxic T cell activity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the cancer context, TIPE2 has emerged as a potent tumor suppressor. Mechanistically, TIPE2 interferes with several oncogenic signaling cascades – notably by binding effectors of the Ras pathway to inhibit downstream molecules such as AKT, ERK1/2, and NF‑κB – ultimately leading to cell cycle arrest (via factors like p27) and promotion of apoptosis. Overexpression of TIPE2 has been shown to suppress tumor cell proliferation, migration, invasion, and the epithelial‑to‑mesenchymal transition in a range of malignancies including hepatocellular carcinoma, gastric cancer, lung cancer, breast cancer, and osteosarcoma. Recent studies have also suggested that alterations in TIPE2 levels might impact the proliferation, migration, and invasiveness of endometrial cells in adenomyosis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in immune regulation and tumor suppression, TIPE2 also fine‑tunes cellular signaling in other contexts. For example, in glioma cells TIPE2 overexpression counteracts hypoxia‑induced epithelial–mesenchymal transition by inhibiting the Wnt/β‑catenin pathway, while in lung cancer, modulation of TIPE2 levels affects cell proliferation and metastatic potential through perturbation of pathways such as Akt/mTOR and NF‑κB. Furthermore, TIPE2 acts as an intrinsic checkpoint during natural killer (NK) cell maturation by suppressing IL‑15–triggered mTOR activation, thereby regulating NK cell activation and antitumor immunity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Guizhong Zhang, Chunyan Hao, Yunwei Lou, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "TIPE2 is a checkpoint of natural killer cell maturation and antitumor immunity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Adv (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/sciadv.abi6515"}], "href": "https://doi.org/10.1126/sciadv.abi6515"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34524845"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34524845"}]}]}]}