From fusion partner to clinical practice: A treatment-oriented framework for transcription factor E3...

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 conducted a comprehensive review of 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 suggest 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 a 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.