miR-301b-3p/ITPKB drives clear cell renal cell carcinoma progression by promoting PARP1/IL8-mediated neutrophil extracellular trap formation

Clear cell renal cell carcinoma (ccRCC) progression is closely associated with pro-tumorigenic neutrophil extracellular traps (NETs) within the tumor microenvironment; however, the upstream molecular mechanisms remain poorly defined. Through integrated multi-omics analysis of ccRCC cohorts, we identified ITPKB as a key downregulated gene associated with NET formation. Subsequent functional validation, including dual-luciferase reporter assays, confirmed that ITPKB is a direct target of the miR-301b-3p. Mechanistically, the loss of ITPKB prevents the ubiquitination-mediated degradation of PARP1, leading to its stabilization and accumulation. Stabilized PARP1 acts as a transcriptional co-activator for NF-κB, triggering a robust secretion of IL-8, which recruits neutrophils and induces their transformation into NETs. These NETs facilitate tumor cell migration and adhesion while conferring resistance to tyrosine kinase inhibitors (sunitinib and sorafenib) and anti-PD-1 therapy. In vivo, the treatment with DNase1 to disrupt NETs effectively reversed this therapeutic resistance. Our findings unveil the miR-301b-3p/ITPKB/PARP1/IL8/NETs axis as a novel mechanistic link between tumor-intrinsic signaling and neutrophil-driven immunosuppression, providing a solid experimental foundation for developing combination therapeutic strategies for advanced ccRCC.