{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRecent studies have established that TOX functions as a master regulator in the differentiation and maintenance of exhausted T cells in settings of chronic antigen exposure. In both tumor‐specific and virus‐specific CD8⁺ T cells, persistent T cell receptor stimulation induces TOX expression via NFAT activation, thereby initiating an exhaustion-associated transcriptional program that upregulates multiple inhibitory receptors while uncoupling these inhibitory features from immediate effector function. Moreover, enforced TOX expression in effector T cells leads to profound epigenetic remodeling, yet genetic deletion of TOX prevents acquisition of exhaustion markers and alters T cell persistence in the tumor microenvironment."}, {"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 thymus, TOX plays a pivotal role in T cell development by inducing changes in coreceptor expression during beta-selection and promoting CD8 lineage commitment during positive selection—processes that appear to involve upregulation of key transcription factors such as Runx3. In malignant contexts, such as T cell acute lymphoblastic leukemia, aberrant TOX expression collaborates with other oncogenic drivers by interfering with DNA repair machinery, thereby increasing genomic instability."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn various cutaneous T cell lymphomas—including mycosis fungoides, Sézary syndrome, and other CTCL variants—TOX is aberrantly overexpressed, serving as both a valuable diagnostic marker and a contributor to oncogenic processes. Elevated TOX levels correlate with disease progression, increased tumor cell survival, and poorer clinical outcomes, as it modulates cell cycle progression, apoptosis, and the expression of other oncogenic markers."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its immunological functions, genetic and epigenetic analyses have implicated TOX in a variety of non–T cell–mediated processes. Polymorphisms and aberrant methylation patterns in TOX and its related family members have been associated with modulation of fetal hemoglobin levels in sickle cell anemia, predisposition to intracranial aneurysms, and antipsychotic-induced weight gain. These findings support a broader role for TOX in modulating gene expression beyond T cell biology."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "21", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn solid tumors and vascular diseases, TOX displays context-dependent roles. In colorectal cancer, reduced TOX expression is associated with advanced disease stages, as TOX acts to suppress mTOR signaling, thereby inhibiting cell proliferation, migration, invasion, and epithelial–mesenchymal transition. Similarly, altered TOX expression has been observed in the tumor thrombus of clear cell renal cell carcinoma and in atherosclerotic lesions, where it appears to modulate the local immune microenvironment and endothelial inflammatory responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "25", "end_ref": "27"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn immune-mediated and autoimmune conditions, increased TOX expression in activated or exhausted T cell subsets has been linked to disease pathogenesis. For instance, in pure red cell aplasia, overactivation of CD8⁺ T cells—with concomitant upregulation of TOX and other immune checkpoint molecules—suggests that TOX may contribute to pathological T cell dysregulation. Emerging evidence of TOX heterogeneity across T cell subsets further underscores its therapeutic potential as both a biomarker and a target for modulating aberrant immune responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "28"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Andrew C Scott, Friederike Dündar, Paul Zumbo, et al. 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