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Background Auto-antibodies (AABs) neutralizing type-I IFNs (IFN-I) were recently uncovered as enriched in critically ill COVID-19 patients, where they act as major negative regulators of anti-viral immune response. IFN-I also play a central role in the regulation of anti-tumor immune response, however, the presence and role of IFN-I neutralizing AABs has never been explored in tumoral context. Here, we evaluated the presence of circulating anti-IFN-I AABs in a large pan-cancer patient cohort and evaluated their functional impact on patient outcome.Methods Anti-IFN-I AABs were screened and quantified in the plasma of patients by ELISA. Neutralization was evaluated using an ISRE-luciferase reporter assay in the presence of varying concentrations of IFN-Is. Patients were stratified according to relapse-free survival evaluated at 1 and 4 years after treatment initiation. RNAseq was performed on FFPE tumor samples to assess IFN-related gene signatures and immune infiltration.Results We evaluated the frequency and neutralizing activity of circulating anti-IFN-I AABs in a cohort of 1,785 cancer patients across several tumor types (melanoma, n=458; glioma, n=270; colon cancer, n=267; diffuse large B-cell lymphoma, n=249; follicular lymphoma, n=107; Hodgkin lymphoma, n=96, stomach cancer, n=90; lung cancer, n=49; others, n=196). Overall, 0.617% of cancer patients scored positive for serum neutralizing anti-IFN-I AABs, and this frequency was similar for all cancer types. Consistent with previous observations in healthy individuals, a significant increase in the frequency of cancer patients with neutralizing anti-IFN-I AABs was observed with ageing. No significant difference was observed between cancer patients and healthy subjects (0.617% vs 0.963%, p-value=0.23). We next analyzed the impact of neutralizing anti-IFN-I AABs on patients’ clinical response to immunotherapy (IT). For this, we analyzed clinical records for n=270 stage IV melanoma patients treated with IT. Surprisingly, we observed a trend towards an enrichment of long-duration responses to ICB (>4 years) in patients positive for neutralizing anti-IFN-I AABs prior treatment initiation. Analysis of validation cohorts is ongoing. To dissect underlying mechanisms, we performed RNAseq analyses on tumor samples from n=22 ICB-treated melanoma patients, and preliminary results show that IFNs and IFN-related genes are specifically downregulated in patients with neutralizing anti-IFN-I AABs, suggesting an in situ shutdown of IFN signaling in the presence of circulating AAB.Conclusions Together, our results highlight a putative role of anti-IFN-I neutralizing AAB in promoting sustained response to ICB, and uncover a previously underestimated role of AAB directed against cytokines in the regulation of anti-tumor immune response in cancer patients.