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Background At the 2025 ASCO Annual Meeting, the KEYNOTE-564 trial confirmed that adjuvant pembrolizumab significantly improves disease-free survival (DFS) and overall survival (OS) in patients with high-risk clear cell renal cell carcinoma (ccRCC). Despite this advance, 52.2% of patients in the placebo arm remained recurrence-free at 5 years, underscoring the need for biomarkers to guide more selective use of adjuvant immunotherapy. In our institutional cohort, we previously observed that low high-density lipoprotein (HDL) levels were associated with inferior DFS in ccRCC patients, prompting further investigation into metabolic factors that may influence recurrence risk. Given increasing recognition of the role of lipid metabolism in ccRCC, we hypothesized that combining clinical lipid profiles with somatic mutations in lipid metabolism pathways could enhance risk stratification for recurrence following nephrectomy.Methods We analyzed a prospective RCC cohort ( NCT03694912) applying the same eligibility criteria used in KEYNOTE-564. A total of 34 patients with intermediate-high or high-risk localized ccRCC were included. Tumor somatic mutation profiling targeting 12 lipid metabolism-related genes (ABCA1, APOA1, APOE, CETP, LIPC, SCARB1, LDLR, HMGCR, NR1H3, NR1H2, SREBF1, SREBF2) was performed in 28 patients with available sequencing data. Baseline HDL-cholesterol levels were measured in all patients. DFS was analyzed using Kaplan-Meier curves and Cox proportional hazards models to assess the impact of HDL-cholesterol, mutation burden, and their combination on recurrence risk.Results At a median follow-up of 30.5 months, 6 out of 34 patients experienced disease recurrence. HDL < 40 mg/dL was significantly associated with inferior DFS ( figure 1, p=0.045). Frequently mutated genes in recurrent cases included ABCA1, NR1H2, and LIPC. When combining HDL and mutation burden, patients with HDL < 40 mg/dL and ≥2 mutations in the lipid metabolism gene panel demonstrated significantly shorter DFS compared to all others (figure 2, p=0.030). In multivariate analysis, HDL-cholesterol remained an independent predictor of DFS (HR=0.87, 95% CI 0.75-0.99, p=0.04).Conclusions Our findings suggest that a combined metabolic biomarker—HDL < 40 mg/dL together with ≥2 somatic mutations in a 12-gene adipose metabolism panel—can identify a subgroup of high-risk ccRCC patients at increased risk of recurrence following surgery. Incorporating such biomarkers into clinical decision-making could help refine patient selection for adjuvant immunotherapy, improving treatment precision. Prospective validation in larger, independent cohorts is warranted.Abstract 147 Figure 1Disease-free survival (DFS) stratified by HDL-cholesterol levelAbstract 147 Figure 2DFS comparison between high-risk and low-risk groups defined by HDL and mutation burden