4548 Background: Clear cell renal cell carcinoma (ccRCC) is biologically heterogeneous, and optimal selection between VEGF-targeted and ICI–based therapies remain an unmet clinical need. Leukemia inhibitory factor (LIF), an IL-6 family cytokine implicated in angiogenesis and immune regulation, is associated with poor prognosis in ccRCC; however, its predictive value for treatment selection has not been defined. Methods: Baseline tumor LIF expression was evaluated in 2,026 patients with metastatic ccRCC across 12 clinical and molecular cohorts, including CheckMate 009/010/025/214, JAVELIN Renal 101, IMmotion150, TCGA-KIRC, CPTAC-3, and institutional datasets. RNA-seq data were batch-corrected, normalized, and immune-deconvoluted (CIBERSORTx). Among 1,306 patients with treatment data, 1,058 with complete clinical covariates were included in treatment-by-biomarker interaction analyses. Results: LIF-high tumors (median cutoff) were associated with younger age (60 vs 63 years, p<0.001) and increased sarcomatoid features (17% vs 8%, p<0.001). A significant treatment-by-LIF interaction was observed for progression-free survival (PFS; interaction p=0.006). High LIF expression predicted inferior PFS on TKI monotherapy (HR 1.26, p<0.001), while this adverse association was absent with ICI-based regimens (monotherapy or combination; HR 0.70, p<0.001). No significant interaction was observed for overall survival. LIF expression discriminated progressive disease from disease control (p<0.001). Immune deconvolution revealed that LIF-high tumors exhibited an inflamed but immunosuppressive microenvironment, characterized by enrichment of macrophages (M0 and M2), neutrophils, and regulatory T cells, with preserved CD8⁺ T-cell infiltration. LIF expression correlated strongly with CXCL8 (R=0.45), and more modestly with FGF2 and VEGFA, consistent with VEGF-independent angiogenic signaling. Conclusions: LIF identifies a biologically distinct subset of metastatic ccRCC characterized by angiogenic and immunosuppressive features and poor outcomes with TKI monotherapy. These data support LIF as a predictive biomarker to inform treatment selection and highlight the LIF/CXCL8 axis as a potential therapeutic target in advanced RCC. Treatment-by-LIF interaction analysis for progression-free survival in metastatic clear cell renal cell carcinoma. Groups N HR 95% CI P-value Full Cohort* 1792 1.09 1.01 – 1.14 0.017 Treatment interaction Model § Main effect (LIF in TKI) 1058 1.26 1.108 - 1.443 <0.001 LIF × IObased (IO and IO+IO) 1058 0.70 0.567 - 0.854 <0.001 LIF × IO+VEGF 1058 0.89 0.73 - 1.079 0.230 LIF × MTORi 1058 0.84 0.689 - 1.035 0.104 Stratified Analyses § : TKI Monotherapy 377 1.27 1.114 - 1.455 <0.001 IO/IO+IO 194 0.87 0.741 - 1.03 0.107 IO+VEGF 364 1.15 0.996 - 1.337 0.057 *Adjusted for IMDC, Age, Sex, Sarcomatoid Features, and Treatment modality. § Adjusted for IMDC, Age, Sex, Sarcomatoid Features.
Saleh et al. (Wed,) studied this question.