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Molecular mechanisms and clinical applications of the immune checkpoint LAG-3
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Abstract:
[Abstract] Lymphocyte activation gene-3 (LAG-3, CD223) plays a pivotal role in regulating T-cell function and maintaining immune homeostasis and is widely recognized as the most promising co-inhibitory immune checkpoint following programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4). LAG-3 is highly expressed on activated T cells and exhausted T cells (TEX) within the tumor microenvironment, where its inhibitory activity constitutes a critical mechanism underlying tumor immune evasion. In contrast to PD-1 and CTLA-4, LAG-3 exhibits distinct regulatory features in modulating T-cell receptor (TCR) signaling strength and restricting T-cell proliferation and effector cytokine production. Consequently, LAG-3 is broadly regarded as one of the most clinically promising immune checkpoint targets beyond PD-1 and CTLA-4. In recent years, advances in the understanding of LAG-3 molecular structure, extracellular ligand interactions (e. g., major histocompatibility complex class Ⅱ [MHC Ⅱ]and fibrinogen-like protein 1 [FGL1]), and intracellular signaling mechanisms have substantially accelerated the development of LAG-3-targeted therapies. Multiple monoclonal antibodies against LAG-3 have entered clinical trials and have demonstrated encouraging therapeutic potential, particularly in combination with PD-1 inhibitors. This review systematically summarizes and discusses the molecular structure of LAG-3, its ligand interactions and downstream signaling pathways, as well as recent advances and future prospects in LAG-3-targeted drugs and clinical therapeutic strategies, with the aim of providing a comprehensive reference for further mechanistic studies and the optimization of future LAG-3-based immunotherapies.
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