Renal cell carcinomas (RCCs) driven by TFE3 rearrangement or TFEB alteration (MiT-RCC) account for up to 40% of pediatric RCCs but are rare in adults. MiT-RCC includes fusion-driven tumors with TFE3 or TFEB rearrangements (translocation RCC, tRCC) and TFEB-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: TFEB-rearranged tumors are often indolent in younger patients, whereas TFEB-amplified RCC, frequently co-amplifying VEGFA, behaves aggressively in older adults. In TFE3-rearranged RCC, fusion partner influences prognosis. Paradoxically, ASPSCR1::TFE3 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, TRIM63 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 TFEB-amplified RCC remains uncertain.

Renal cell carcinomas (RCCs) driven by TFE3 rearrangement or TFEB alteration (MiT-RCC) account for up to 40% of pediatric RCC but are rare in adults. MiT-RCC includes fusion-driven tumors with TFE3 or TFEB rearrangements (translocation RCC, tRCC) and TFEB-amplified RCC. Morphologic heterogeneity and historical exclusion from trials have limited evidence-based management. We reviewed literature through January 2026 to summarize molecular biology, pathology, clinical behavior, and systemic therapy. MiT-RCC comprises biologically distinct entities: TFEB-rearranged tumors are often indolent in younger patients, whereas TFEB-amplified RCC, frequently co-amplifying VEGFA, behaves aggressively in older adults. In TFE3-rearranged RCC, fusion partner influences prognosis. Paradoxically, ASPSCR1–TFE3 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, TRIM63 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 TFEB-amplified RCC remains uncertain.

Systemic treatment of advanced renal cell carcinoma (RCC) after kidney transplantation requires balancing cancer control against allograft injury and immunosuppression. We searched PubMed, Ovid Embase, Scopus, Web of Science, and ClinicalTrials.gov in April 2026, with reruns on 13 August and 19 October 2026. We separated RCC-specific transplant reports from mixed-cancer transplant and non-transplant studies. Direct evidence comprised mainly case reports and retro-spective cohorts with incomplete outcomes and possible overlap. No prospective kidney-transplant-specific RCC study was identified. Vascular endothelial growth factor receptor–targeted tyrosine kinase inhibitors achieved tumor control in selected reports, but renal toxicity and interactions limited safety conclusions. Indications for mechanistic target of rapamycin in-hibitors (RCC treatment or immunosuppression) were often unclear. Concurrent therapies com-plicated response attribution. Immune checkpoint inhibitor outcomes ranged from tumor control with preserved graft function to rejection, irreversible graft loss, dialysis, graft intolerance, or nephrectomy. An unvalidated multidisciplinary framework integrates tumor site and lineage, histology, performance status, immunosuppression, and patient priorities. It distinguishes func-tioning or failing grafts, irreversibly failed retained grafts, and absence of allografts, states that change treatment trade-offs and outcome interpretation. Comparative evidence establishes nei-ther a preferred RCC sequence nor a graft-protective immunosuppressive regimen. Prospective studies should prioritize paired, state-specific cancer and transplant outcomes.