Tumour-Derived Extracellular Vesicles Reprogramme Tumour-Associated Macrophages Into Immunosuppressive Phenotype via NOD1 Signalling in Clear Cell Renal Cell Carcinoma

  • J Extracell Vesicles. 2026 Jun;15(6):e70317. doi: 10.1002/jev2.70317.
Xiu-Wu Pan  1 ,  Mu-Chen Li  1 ,  Tian-Yue Yang  1 ,  Yi-Fan Liu  1 ,  Jia-Lin Zhou  1 ,  Yi-Fan Tang  1 ,  Hong-Feng Zheng  1 ,  Jian-Gui Liu  1 ,  Zi-Chang Liu  1 ,  Wen-Jie Ma  1 ,  Wen-Yan Li  1 ,  Zi-Xuan Gong  1 ,  Shun Zhang  1 ,  Hang-Biao Zhang  1 ,  Bing-Nan Lu  1 ,  Yun-Tao Yao  1 ,  Dong-Hao Lyu  1 ,  Guan-Yu Zhu  1 ,  Yuan-Bo Zong  1 ,  Han-Lin Yao  1 ,  Ai-Ping Zhang  1 ,  Jin Zeng  2 ,  Si-Tu Xiong  2 ,  Ke-Qin Dong  1 ,  Wang Zhou  1 ,  Bin Fu  2 ,  Xin-Gang Cui  1
Affiliations
  • 1. Department of Urology, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 2. Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
PMID: 42226559 DOI: 10.1002/jev2.70317
Abstract

Clear cell renal cell carcinoma (ccRCC)-derived extracellular vesicles (EVs) play a pivotal role in myeloid cell differentiation toward immunosuppressive phenotypes, yet the underlying mechanisms remain poorly understood. Through integrated single-nucleus RNA Sequencing, EV proteomics, and phenotype validation, we identified NOD1, a pattern recognition receptor (PRR), as a critical mediator of EV-driven macrophage differentiation. Clinically, NOD1 overexpression in ccRCC tissues correlated with increased immunosuppressive macrophage infiltration, immune checkpoint inhibitors (ICIs) therapy resistance, and poor prognosis. Mechanistically, ccRCC-EVs enriched with SCRIB, a Rho GTPase activator, triggered sustained NOD1 activation in macrophages via Rho GTPase signalling. Crucially, NOD1 signalling converged on interferon regulatory factor 4 (IRF4), whose expression might be dynamically regulated through NF-κB activation and MITF suppression. Furthermore, inhibition of NOD1 promotes the therapeutic effect of ICIs in vivo. Our findings unveil a novel EV-mediated immune evasion mechanism in ccRCC and propose the SCRIB-NOD1-IRF4 axis as a therapeutic target to restore anti-tumour immunity.

Keywords
IRF4; NOD1 signalling; SCRIB; clear cell renal cell carcinoma; extracellular vesicles.
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