<p>ICIs resistance presents a significant challenge in clinical practice. Circulating extracellular vesicles circRNAs are promising biomarkers for cancer diagnosis and treatment. This study aimed to determine the oncogenic role of circulating extracellular vesicles circ_PPAPDC1A in ICIs resistance diagnosis and prognostic analysis of NSCLC. We used a co-culture system of NSCLC cells and T cells, and a mice xenograft assay, to evaluate the effect of circ_PPAPDC1A on anti-PD-1 antitumor activity. A multicenter cohort study of 40 patients analyzed the associations between extracellular vesicles circ_PPAPDC1A and ICIs resistance. In vitro, circ_PPAPDC1A reduced the sensitivity of NSCLC cells to ICIs by promoting proliferation and inhibiting apoptosis. In vivo, circ_PPAPDC1A promoted NSCLC progression and induced CD8⁺ T-cell exhaustion. Clinical samples showed circ_PPAPDC1A upregulation in NSCLC patients with ICIs resistance, high diagnostic efficiency (AUC = 0.98), and higher expression associated with shorter PFS. Circulating extracellular vesicles circ_PPAPDC1A may serve as a predictive biomarker for ICIs resistance diagnosis and prognostic analysis.</p>