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Through integrated single\u2010nucleus RNA sequencing, EV proteomics, and phenotype validation, we identified NOD1, a pattern recognition receptor (PRR), as a critical mediator of EV\u2010driven 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\u2010EVs 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\u2010\u03baB activation and MITF suppression. Furthermore, inhibition of NOD1 promotes the therapeutic effect of ICIs in vivo. Our findings unveil a novel EV\u2010mediated immune evasion mechanism in ccRCC and propose the SCRIB\u2010NOD1\u2010IRF4 axis as a therapeutic target to restore anti\u2010tumour immunity.<\/jats:p>","DOI":"10.1002\/jev2.70317","type":"journal-article","created":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T06:20:14Z","timestamp":1780381214000},"source":"Crossref","is-referenced-by-count":1,"title":["Tumour\u2010Derived Extracellular Vesicles Reprogramme Tumour\u2010Associated Macrophages Into Immunosuppressive Phenotype via NOD1 Signalling in Clear Cell Renal Cell Carcinoma"],"prefix":"10.1002","volume":"15","author":[{"given":"Xiu\u2010wu","family":"Pan","sequence":"first","affiliation":[{"name":"Department of Urology, Xinhua Hospital School of Medicine, Shanghai Jiao Tong University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mu\u2010chen","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Urology, Xinhua Hospital 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