{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTNFRSF18, also known as glucocorticoid‐induced tumor necrosis factor receptor (GITR), is a key immune checkpoint molecule predominantly expressed on activated T cells and regulatory T cells (Tregs). Its engagement modulates T‐cell survival, activation, and differentiation, influencing cytokine production and downstream signaling cascades such as NF‐κB through interactions with adaptor proteins like TRAFs. In multiple studies, elevated or induced GITR expression has been associated with both enhanced effector functions and alterations in Treg activity, delineating a dual role in balancing immune activation and suppression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the realm of cancer immunology, GITR engagement is being exploited to counteract tumor‐mediated immune suppression. Agonistic targeting of GITR has been shown to reduce the suppressive capacity of Tregs while amplifying effector T‐cell responses against tumor antigens. This dual mechanism is further complemented by GITR’s impact on innate immune cells such as natural killer (NK) cells, although its effects may vary between murine and human systems. Investigations in hematologic malignancies, solid tumors, and models of hepatocellular and lymphoid cancers underscore the potential of GITR modulation as part of novel cancer vaccine strategies and combinatorial immunotherapeutic regimens."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond oncology, alterations in the GITR–GITRL axis play a significant role in autoimmune and inflammatory disorders. Dysregulated expression or function of GITR can impair the suppressive capacity of Tregs, contributing to the pathophysiology of diseases such as systemic lupus erythematosus, type 1 diabetes, and various immunodeficiency syndromes. In these contexts, aberrant GITR signaling correlates with heightened pro-inflammatory cytokine production and disease severity, positioning it as a potential biomarker for immune dysregulation in both pediatric and adult patient populations."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, GITR signaling is intricately linked to both post‐receptor signal modulation and epigenetic regulation. Structural and methylation studies have revealed that alterations in the GITR promoter can lead to gene silencing in malignancies such as multiple myeloma, affecting sensitivity to therapeutic agents like bortezomib. In parallel, changes in GITR expression have been linked to autoimmune thyroid diseases and atopic conditions, where modulation of Treg survival and effector cytokine balance is critical. Such insights into receptor–ligand interactions and epigenetic modifications further advance our understanding of how GITR regulates immune homeostasis and autoimmunity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "26", "end_ref": "34"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRecent advances have expanded the functional repertoire of TNFRSF18 to encompass roles in additional immune cell subsets and clinical applications. Upregulation of GITR on basophils in response to IL-3 stimulation enhances Th2 cytokine production, while its modulation in follicular helper T cells influences B-cell isotype switching and humoral immunity. Moreover, altered GITR signaling has been associated with atherosclerotic plaque vulnerability and is under investigation for its utility in refining dosing strategies of immune-modulatory therapies. Collectively, these findings underscore TNFRSF18/GITR as a central regulator of immune responses with a wide-ranging impact on tumor immunity, autoimmunity, and beyond."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "35", "end_ref": "40"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Alexander Pedroza-Gonzalez, Cornelis Verhoef, Jan N M Ijzermans, et al. 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