基质纳米排列通过TRPV2机械门控编程巨噬细胞囊泡免疫
Matrix nanoalignment programs macrophage vesicular immunity through TRPV2 mechanogating.
摘要(中文译文)
细胞外基质（ECM）在肿瘤进展过程中经历广泛的结构重塑，产生纳米级排列线索，深刻影响免疫细胞的行为。然而，ECM纳米结构是否直接编程其免疫分泌功能仍鲜有明确。在此，我们开发了一种磁可切换水凝胶，能够在不改变整体硬度或组成的情况下，可逆地、按需调控纳米级配体排列。利用该平台，我们揭示了肿瘤相关巨噬细胞（TAMs）中的一条机械转导通路，即基质纳米排列增强整合素β1依赖性机械感知和瞬时受体电位阳离子通道V亚家族成员2（TRPV2）依赖性Ca信号，从而促进磷酸肌醇3-激酶（PI3K）-Ras相关蛋白11a（Rab11a）相关的小细胞外囊泡（sEV）释放约十倍。除了增加囊泡产量外，PI3K-雷帕霉素靶蛋白复合物2相关信号还改变了sEV的颗粒归一化货物谱，优先富集免疫调节分子，包括M2促进性细胞因子和miR-181a-5p。这些sEV将巨噬细胞重编程为免疫抑制性M2样表型，抑制细胞毒性CD8 T细胞浸润，并在体内加速黑色素瘤进展。重要的是，选择性破坏TRPV2-Rab11a轴或药理学减弱ECM重塑可恢复抗肿瘤免疫并限制肿瘤生长。总之，我们的研究结果表明，ECM纳米结构足以在确定的基质环境中调控巨噬细胞sEV编程，并确定TRPV2相关机械转导是基质重塑肿瘤中潜在的治疗脆弱点。
Abstract
The extracellular matrix (ECM) undergoes extensive architectural remodeling during tumor progression, generating nanoscale alignment cues that profoundly influence behaviors of immune cells. However, whether ECM nanoarchitecture directly programs their immune secretory functions remains poorly defined. Here, we develop a magnetically switchable hydrogel that enables reversible, on-demand modulation of nanoscale ligand alignment without altering bulk stiffness or composition. Using this platform, we uncover a mechanotransduction pathway in tumor-associated macrophages (TAMs) whereby matrix nanoalignment enhances integrin β1-dependent mechanosensing and transient receptor potential cation channel subfamily V member 2 (TRPV2)-dependent Ca signaling, thereby promoting phosphoinositide 3-kinase (PI3K)-Ras-related protein 11a (Rab11a)-associated small extracellular vesicle (sEV) release by approximately tenfold. Beyond increasing vesicle output, PI3K-mechanistic target of rapamycin complex 2-associated signaling altered the particle-normalized cargo profile of sEVs, with preferential enrichment of immunoregulatory molecules, including M2-promoting cytokines and miR-181a-5p. These sEVs reprogram macrophages toward an immunosuppressive M2-like phenotype, suppress cytotoxic CD8 T-cell infiltration, and accelerate melanoma progression in vivo. Importantly, selective disruption of the TRPV2-Rab11a axis or pharmacological attenuation of ECM remodeling restores antitumor immunity and restricts tumor growth. Together, our findings demonstrate that ECM nanoarchitecture is sufficient to regulate macrophage sEV programming in a defined matrix environment and identify TRPV2-associated mechanotransduction as a potential therapeutic vulnerability in matrix-remodeled tumors.
如何引用
AMA
Bohan Yin, Guangli Xiang, Ziqi Zhang, Limeng Zheng, Runyao Wang, Qin Zhang, et al. Matrix nanoalignment programs macrophage vesicular immunity through TRPV2 mechanogating.. Bioactive materials. 2027; doi:10.1016/j.bioactmat.2026.09.011.
APA
Bohan Yin, Guangli Xiang, Ziqi Zhang, Limeng Zheng, Runyao Wang, Qin Zhang, et al (2027). Matrix nanoalignment programs macrophage vesicular immunity through TRPV2 mechanogating.. Bioactive materials. https://doi.org/10.1016/j.bioactmat.2026.09.011
GB/T 7714
Bohan Yin, Guangli Xiang, Ziqi Zhang, Limeng Zheng, Runyao Wang, Qin Zhang, et al. Matrix nanoalignment programs macrophage vesicular immunity through TRPV2 mechanogating.[J]. Bioactive materials, 2027 doi:10.1016/j.bioactmat.2026.09.011.
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