TFE3-Rearranged and TFEB-Altered Renal Cell Carcinomas: Molecular Landscape and Therapeutic Advances

Renal cell carcinomas (RCCs) driven by <i>TFE3</i> rearrangement or <i>TFEB</i> alteration (MiT-RCC) account for up to 40% of pediatric RCCs but are rare in adults. MiT-RCC includes fusion-driven tumors with <i>TFE3</i> or <i>TFEB</i> rearrangements (translocation RCC, tRCC) and <i>TFEB</i>-amplified RCC. Morphologic heterogeneity and historical exclusion from trials have limited evidence-based management. We reviewed the literature through January 2026 to summarize molecular biology, pathology, clinical behavior, and systemic therapy. MiT-RCC comprises biologically distinct entities: <i>TFEB</i>-rearranged tumors are often indolent in younger patients, whereas <i>TFEB</i>-amplified RCC, frequently co-amplifying <i>VEGFA</i>, behaves aggressively in older adults. In <i>TFE3</i>-rearranged RCC, fusion partner influences prognosis. Paradoxically, <i>ASPSCR1</i>::<i>TFE3</i> fusions have the poorest natural history, yet fusion-annotated cohorts suggest these tumors may derive particular benefit from immune checkpoint inhibitor (ICI) plus VEGF receptor tyrosine kinase inhibitor (VEGFR-TKI) combinations. Diagnostic advances including GPNMB immunohistochemistry, <i>TRIM63</i> RNA in situ hybridization, and sequencing-based fusion panels improve detection of cryptic alterations. First-line ICI + VEGFR-TKI combinations are increasingly favored for metastatic tRCC in eligible patients, while optimal management of <i>TFEB</i>-amplified RCC remains uncertain.