AbstractBackgroundImmunotherapy (IO) plus tyrosine kinase inhibitor (TKI) emerged as standard first‐line therapy for advanced renal cell carcinoma (RCC). The heme Oxygenase 1 (HMOX1) pathway is involved in tumor development and treatment resistance, which may affect the efficacy of TKI + IO.MethodsTwo cohorts from our center (ZS‐MRCC, ZS‐HRRCC), one cohort from clinical trial (JAVELIN Renal 101) and the Cancer Genome Atlas (TCGA‐KIRC) were enrolled. HMOX1 pathway signatures were determined for each sample by RNA‐sequencing and gene set enrichment analysis. Immune infiltration was evaluated by flow cytometry. Response and progression‐free survival (PFS) were set as primary endpoints.ResultsPatients of low‐HMOX1 signature showed higher objective response rate (43.5% vs. 27.3%) in ZS‐MRCC cohort and longer PFS in both cohorts (ZS‐MRCC cohort,p= 0.019; JAVELIN‐101 cohort,p= 0.036). Patients in the high‐HMOX1 signature arm also showed greater clinical benefit from TKI + IO, rather than TKI monotherapy (p< 0.001). In high‐HMOX1 signature RCC tissues, CD8+T cells showed a dysfunctional phenotype with decreased GZMB expression (Spearman's ρ = −0.32,p= 0.045). A risk score based on HMOX1 signature was further constructed by random forest approach, involving HMOX1 signature and immunologic features. In patients with a low risk level, TKI + IO combination therapy demonstrated longer PFS than TKI monotherapy (p< 0.001), however in individuals with a high risk score group, these two regimens did not give different advantages.ConclusionsOur study identified the HMOX1 pathway signature was a potential prognostic factor of progression‐free survival for TKI + IO combination therapy in the advanced RCC in different cohort, especially in first‐line management of mRCC in the Javelin 101 cohort. Moreover, HMOX1 signature was associated with T‐cell function in tumor environment.