78 Dietary Fructose Intake and Tumoral Fructose-Metabolism Gene Expression in Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Blockade

Background Diet and metabolism are increasingly recognized as modifiable determinants of response to immune checkpoint blockade (ICB), yet the impact of specific metabolites in metastatic renal cell carcinoma (mRCC) remains poorly defined. Preclinical data in melanoma link fructose consumption to ICB resistance. In our prior work, however, higher dietary fructose showed a univariable association with longer overall survival (OS) in a small RCC cohort. The fructose-metabolism enzyme ketohexokinase (KHK) is downregulated in clear cell RCC cells, raising the possibility that tumor-level fructose handling is biologically relevant. We evaluated whether dietary fructose intake and tumoral expression of fructose-metabolism genes are associated with outcomes in patients with mRCC receiving ICB. Methods We conducted a retrospective analysis of a prospectively collected cohort of patients with mRCC treated with ICB. Dietary intake was assessed using the validated Harvard Willett Food Frequency Questionnaire. Fructose intake was modeled as a continuous variable in raw (g/d) and energy-adjusted (g/d per 1,000 kcal) form. Associations with progression-free survival (PFS) and OS were evaluated by univariable (UV) and multivariable (MV) Cox proportional hazards regression, adjusted for International Metastatic RCC Database Consortium (IMDC) risk, histology, and treatment regimen. Kaplan-Meier curves were used to visualize associations of fructose intake and survival outcomes. To assess biologic plausibility, tumoral expression of fructose-metabolism enzymes, specifically KHK, was examined in the TCGA Kidney Renal Clear Cell Carcinoma (KIRC) PanCancer Atlas and in IMmotion151, CheckMate 214, and JAVELIN Renal 101. Results Sixty-eight patients with mRCC were included. Median age was 64 years, 74% were male, and 18% had non-clear cell histology; 57% received an ICB+TKI regimen and 43% a dual ICB regimen. Median dietary fructose intake was 17.0 g/d (10.2 g/d per 1,000 kcal). Fructose intake was not correlated with IMDC risk score, ECOG performance status, or BMI. Higher fructose intake was significantly associated with longer OS in both UV (log-rank p < 0.001) and MV analyses: each 10 g/d increase in raw fructose was associated with an adjusted hazard ratio (aHR) for OS of 0.47 (95% CI 0.27–0.83, p = 0.009), with a directionally concordant energy-adjusted estimate (aHR 0.37 per 10 g/d per 1,000 kcal, 95% CI 0.14–0.98, p = 0.047). No association was observed with PFS in either model. At the tumor level, higher KHK expression trended towards association with longer survival across all evaluable RCC datasets, reaching statistical significance in the TCGA-KIRC (OS HR 0.70, 95% CI 0.58–0.85, p < 0.001), both arms IMmotion151 (atezolizumab + bevacizumab arm, PFS HR 0.85, 95% CI 0.75–0.96, p = 0.007; sunitinib arm, PFS HR 0.70, 95% CI 0.63-0.79, p < 0.001) and the sunitinib arm of JAVELIN Renal 101 (0.65, 95% CI 0.56-0.75, p < 0.001). Effect sizes were similar or greater in TKI-containing arms, suggesting a predominantly prognostic rather than ICB-specific role. Conclusions In our mRCC cohort treated with ICB-based therapy, higher dietary fructose intake was associated with longer OS. Concordantly, higher tumoral KHK expression was associated with improved survival outcomes across multiple public RCC datasets, suggesting a biological relationship between fructose metabolism and favorable clinical outcomes in RCC. Whether RCC tumors with active fructose metabolism may represent a less aggressive disease phenotype warrants further investigation. Mechanistic studies linking dietary fructose to RCC tumor biology are ongoing and may inform dietary strategies in mRCC.