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Background While immune checkpoint inhibitor (ICI)-based therapy has shown promising efficacy in patients with metastatic non-clear cell renal cell carcinoma (nccRCC) in the first-line setting, the optimal treatment following disease progression remains undefined. We aimed to investigate the efficacy, safety, and predictive markers of ICI rechallenge in this population.Methods 39 patients with metastatic nccRCC who received ICI rechallenge were enrolled. Key outcomes included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival. Whole exome sequencing, bulk RNA sequencing, and multiplex immunofluorescence (mIF) were performed to further explore potential biomarkers associated with the efficacy of ICI-rechallenge among nccRCC.Results Following ICI-rechallenge, the cohort demonstrated a median PFS of 11.8 months, an ORR of 13.9% and a DCR of 69.4%. Among clinicopathological variables, the fumarate hydratase-deficient renal cell carcinoma subtype was the only factor associated with the potential clinical benefit from ICI-rechallenge. Transcriptomic analysis revealed that an enrichment of B cells and central memory T cell signatures was associated with longer PFS (21.3 vs 7.9 months). Notably, patients with a higher mature intratumoral tertiary lymphoid structure (m-iTLS) score assessed by mIF showed higher ORR (50.0% vs 0.0%) and longer PFS (28.2 vs 5.0 months) compared with those with a lower m-iTLS score. In terms of safety, ICI rechallenge was generally well tolerated, with no accumulation or treatment-related deaths observed.Conclusions ICI rechallenge may offer favorable clinical benefit and acceptable safety in patients with metastatic nccRCC. Higher density of mature iTLSs correlated with the efficacy of ICI-rechallenge but warrants further validation.