[摘 要] 淋巴细胞活化基因-3（LAG-3，又称CD223），在调控T细胞功能和维持免疫稳态中发挥关键作用，被公认为继程序性 死亡蛋白-1（PD-1）和细胞毒性T淋巴细胞抗原-4（CTLA-4）之后最具潜力的共抑制性免疫检查点。LAG-3在活化的T细胞和肿 瘤微环境中的耗竭性T细胞（TEX）表面高表达，其抑制功能是肿瘤逃逸免疫监视的关键机制。与PD-1和CTLA-4相比，LAG-3在 调控 T 细胞受体（TCR）信号强度、限制 T 细胞增殖及效应因子分泌方面具有独特的作用模式，因此被普遍认为是继 PD-1 和 CTLA-4之后最具临床开发潜力的免疫检查点靶点之一。近年来，随着对LAG-3分子结构、胞外区配体相互作用[如主要组织相 容性复合体Ⅱ类分子（MHCⅡ类分子）、纤维蛋白原样蛋白1（FGL1）等]以及胞内信号转导机制认识的不断深入，多种靶向LAG-3 的单克隆抗体已进入临床研究阶段，并在与PD-1抑制剂联合治疗中显示出良好的应用前景。本文将系统地总结并探讨LAG-3 的分子结构、配体相互作用和信号通路的分子机制，以及其靶向药物和临床疗法的最新研究进展和应用前景，旨在为LAG-3靶向 疗法的深入研究和未来临床策略优化提供有力的参考。

[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.

[基金项目] 昌平实验室资助