{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nLymphocyte‐activation gene‐3 (LAG3) is a critical immune checkpoint receptor widely expressed on activated T cells and natural killer cells that plays a central role in dampening immune responses within the tumor microenvironment. Multiple studies in cancer settings—including ovarian cancer, non–small cell lung cancer, melanoma, Hodgkin lymphoma, and other malignancies—have demonstrated that LAG3 is frequently co‐expressed with other inhibitory receptors such as PD‐1 on tumor‐infiltrating lymphocytes. This coexpression is associated with T cell exhaustion, impaired cytokine production, reduced proliferative capacity, and the enrichment of regulatory T cell subsets, all of which contribute to tumor immune evasion. In addition, LAG3 engagement via its natural ligands (for example, stable peptide–MHC class II complexes) or through soluble forms modulates antigen presentation by dendritic cells and even can directly protect tumor cells from apoptosis. Together, these findings not only reinforce the negative regulatory function of LAG3 but also underscore its prognostic significance in several cancers and its potential as a therapeutic target, as demonstrated by dual blockade strategies that enhance antitumor immunity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond oncology, LAG3 has been implicated in the context of neurodegenerative and infectious diseases as well as autoimmune disorders. In early studies of Parkinson’s disease, LAG3 was reported to bind α‐synuclein fibrils and mediate their endocytosis, a process initially proposed to contribute to the spread of pathology; however, subsequent investigations have raised questions regarding its neuronal expression and direct involvement in neurodegeneration. In chronic viral infections such as HIV and hepatitis B, the upregulation of LAG3 is associated with T cell dysfunction and impaired pathogen‐specific immune responses. In parallel, genetic studies linking LAG3 variants to an increased risk of multiple sclerosis and type 1 diabetes highlight its broader role in maintaining immune tolerance and homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "25", "end_ref": "31"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, LAG3 exhibits a unique signaling mode compared with other co‐inhibitory receptors. It preferentially binds stable peptide–MHC class II complexes without overtly competing with the CD4 co‐receptor, and its intracellular domain transmits inhibitory signals that curtail T cell activation. The regulation of LAG3 surface expression involves intricate trafficking from lysosomal compartments to the plasma membrane—a process governed by protein kinase C signaling and specific cytoplasmic motifs. Moreover, engagement of LAG3 on antigen-presenting cells, such as dendritic cells, can trigger rapid maturation and the upregulation of costimulatory molecules, thereby influencing the balance between activation and tolerance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "32", "end_ref": "34"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThese mechanistic insights have spurred the development of innovative therapeutic approaches targeting the LAG3 pathway. Clinical strategies now include the use of LAG3‐blocking antibodies—often in combination with PD‐1 inhibitors—to reinvigorate T cell responses in cancers such as renal cell carcinoma, breast cancer, and multiple myeloma. Furthermore, soluble LAG3 fusion proteins are under evaluation as novel immunostimulatory agents, while alterations in LAG3 processing (for example, noncleavable mutants) have been implicated in resistance to checkpoint blockade therapies. Epigenetic regulation of LAG3 expression, along with its emerging role as a predictive biomarker, supports its incorporation into next‐generation immuno‐oncology regimens and highlights its potential in overcoming tumor-induced immune tolerance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "35", "end_ref": "39"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Junko Matsuzaki, Sacha Gnjatic, Paulette Mhawech-Fauceglia, et al. 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