ARTICLE ABSTRACTThe response rates upon neoadjuvant immune checkpoint blockade (ICB) in stage III melanoma are higher as compared to stage IV disease. Given that successful ICB depends on systemic immune response, we hypothesized that systemic immune suppression might be a mechanism responsible for lower response rates in late-stage disease, and also potentially with disease recurrence in early-stage disease. Plasma and serum samples of cohorts of melanoma patients were analyzed for circulating proteins using mass spectrometry proteomic profiling and Olink proteomic assay. A cohort of paired samples of patients with stage III that progressed to stage IV disease (n=64) was used to identify markers associated with higher tumor burden. Baseline patient samples from the OpACIN-neo study (n=83) and PRADO study (n=49; NCT02977052) were used as two independent cohorts to analyze whether the potential identified markers are also associated with disease recurrence after neoadjuvant ICB therapy. When comparing baseline proteins overlapping between patients with progressive disease and patients with recurrent disease, we found leucine-rich alpha-2-glycoprotein 1 (LRG1) to be associated with worse prognosis. Especially non-responder patients to neoadjuvant ICB (OpACIN-neo) with high LRG1 expression had a poor outcome with an estimated 36-month event-free survival of 14% as compared to 83% for non-responders with a low LRG1 expression (P = 0.014). This finding was validated in an independent cohort (P = 0.0021). LRG1 can be used as a biomarker to identify patients with high risk for disease progression and recurrence, and might be a target to be combined with neoadjuvant ICB.