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

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.