From fusion partner to clinical practice: A treatment-oriented framework for transcription factor E3 (TFE3)-rearranged renal carcinoma

Transcription factor E3-rearranged renal cell carcinoma ( TFE3 -rRCC) is a rare, fusion-driven malignancy characterized by marked biological heterogeneity, diagnostic complexity, and suboptimal clinical outcomes under standard RCC therapies. Although several molecular studies have highlighted the importance of fusion partner diversity, these findings remain fragmented and incompletely integrated into clinical practice. In this review, we systematically reviewed genomic, transcriptomic, proteomic, and clinical studies on TFE3 -rRCC. We synthesized evidence from retrospective cohorts, multi-omics analyses, and preclinical models to elucidate the molecular structure of recurrent diseases, protein-level signaling pathways, tumor microenvironment status, and emerging modalities of treatment response. We found that TFE3 -rRCC is a fusion-defined disease family with substantially more structural variations than point mutations. The coding features of fusion partners result in functionally distinct modules that reshape transcriptional regulation, RNA processing, protein homeostasis, and mitochondrial quality control, resulting in reproducible protein-level subtypes and immune-vascular "fingerprints". These features support diagnostic and therapeutic hypotheses based on fusion partner regulation, including varying sensitivities to angiogenesis-targeting and immune-targeting strategies. Further, we suggest a combined diagnostic pathway with respect to pathology, molecular tests, computational techniques, and partner-guided clinical trial framework for future validation. Taken together, this review formalizes a fusion partner-informed framework that links molecular mechanism with clinical investigation. By defining evidentiary boundaries and validation pathways, it provides a roadmap for translating mechanistic insight into rigorous evidence-based management of TFE3 -rRCC. It outlines a partner-informed framework for TFE3 -rRCC. Diagnosis follows a stepwise pathway—morphology, TFE3 IHC, FISH confirmation, and RNA sequencing—to achieve fusion partner–resolved classification. Distinct partners encode specific pathway and microenvironmental states: ASPSCR1-TFE3 aligns with angiogenic–inflammatory features and ICI-TKI hypotheses; PRCC-TFE3 implicates mitophagy and metabolic vulnerabilities; SFPQ/NONO-TFE3 associate with splice-transcription coupling and mTOR rewiring. Integrated monitoring supports partner-stratified, mechanism-based clinical investigation. AI: Artificial intelligence; ASPSCR1 : Alveolar soft part sarcoma chromosome region, candidate 1; FISH: Fluorescence in situ hybridization; ICI: Immune checkpoint inhibitor; IHC: Immunohistochemistry; mTOR: Mammalian target of rapamycin; PRCC: Proline-rich mitotic checkpoint control; SFPQ/NONO : Splicing factor proline and glutamine rich/non-POU domain containing octamer binding; TFE3 -rRCC: TFE3 -rearranged renal cell carcinoma; TKI: Tyrosine kinase inhibitor. • Transcription factor E3 ( TFE3 )-rearranged renal cell carcinoma is a fusion-driven disease family with marked pathway and microenvironmental heterogeneity. • Fusion partner identity determines distinct molecular mechanisms shaping signaling circuits and tumor microenvironment states. • Proteogenomic and mechanistic evidence support partner-informed diagnostic classification beyond histology alone. • A partner-stratified framework links molecular fingerprints to therapeutic hypotheses and trial design.