Chen Shirui, Chen Junjie, Kong Yaojie, Li Henghui, Chen Zhinan, Luo Lingjie, Wu Yanwei, Chen Liang
Department of Cell Biology, National Translational Science Center for Molecular Medicine, Fourth Military Medical University, Xi'an 710032, China.
State Key Laboratory of New Targets Discovery and Drug Development for Major Diseases, Xi'an 710032, China.
Int J Mol Sci. 2025 May 2;26(9):4332. doi: 10.3390/ijms26094332.
Various inhibitors targeting T-cell immunoglobulin and mucin-containing molecule 3 (TIM3) aimed at reversing T-cell exhaustion for better immunotherapy outcomes have demonstrated limited clinical efficacy as monotherapy, with the underlying mechanisms remaining ambiguous. TIM3 is markedly expressed in dendritic cells (DCs), and the inconsistent research findings on its role in myeloid cells underscore its vital function within DCs. Through the establishment of an in vitro differentiation model generating mature dendritic cells (mDCs) under TIM3-targeted interventions, combined with an RNA sequencing analysis, this investigation systematically examined TIM3-mediated regulation and ligand interactions in human primary DCs. The findings indicate that TIM3 inhibition hinders DC maturation, which subsequently diminishes the antigen-presenting capacity of DCs, ultimately leading to immune suppression in T cells. These findings collectively establish TIM3 as a regulator of DC differentiation that promotes DC maturation while optimizing the antigen-processing and presentation capacity. This study elucidates the rationale behind the suboptimal efficacy of TIM3 inhibitors and advocates for retaining TIM3 signaling pathways in DCs.
各种旨在逆转T细胞耗竭以获得更好免疫治疗效果的靶向T细胞免疫球蛋白和含粘蛋白分子3（TIM3）的抑制剂作为单一疗法显示出有限的临床疗效，其潜在机制仍不明确。TIM3在树突状细胞（DCs）中显著表达，关于其在髓样细胞中作用的研究结果不一致，凸显了其在DCs中的重要功能。通过建立在TIM3靶向干预下产生成熟树突状细胞（mDCs）的体外分化模型，并结合RNA测序分析，本研究系统地研究了TIM3在人原代DCs中介导的调控和配体相互作用。研究结果表明，TIM3抑制会阻碍DC成熟，进而降低DC的抗原呈递能力，最终导致T细胞免疫抑制。这些研究结果共同确立了TIM3作为DC分化的调节因子，它在促进DC成熟的同时优化抗原处理和呈递能力。本研究阐明了TIM3抑制剂疗效欠佳的背后原理，并主张保留DCs中的TIM3信号通路。
