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#TFE3-Rearranged and TFEB-Altered #Renal Cell Carcinomas: Molecular Landscape and Therapeutic Advances
🧑‍⚕️by Mikel Portu Grive, Mario Balsa et al.
Full text➡️ www.mdpi.com/2072-6694/18...
#MiTRCC #GeneFusion #ICI #CancersMDPI
Figure 1. Integrated mechanistic model of MiT-RCC driven by TFE3 and TFEB alterations. In TFE3-rearranged RCC, most fusions join a 5′ partner gene to the 3′ portion of TFE3, preserving the C-terminal DNA-binding and dimerization domains and promoting constitutive nuclear activity; TFEB-rearranged tumors are driven by analogous transcriptional deregulation, whereas TFEB-amplified RCC is biologically distinct. These events activate a core MiT/TFE transcriptional program that rewires tumor cell metabolism and stress-adaptation pathways. In fusion-driven translocation RCC (tRCC), TFE3/TFEB fusions induce upregulation of PPARGC1A (PGC-1α), promoting mitochondrial biogenesis and increased dependency on oxidative phosphorylation (OXPHOS), which creates context-specific metabolic vulnerabilities. In parallel, sustained activation of the mTOR-lysosome axis enhances lysosomal biogenesis and autophagy, supporting tumor survival under metabolic stress and reflecting partial uncoupling of MiT/TFE activity from canonical nutrient-sensing control. Crosstalk with hypoxia signaling through the EGLN1 (PHD2)-HIF-1α axis enables adaptive metabolic switching and, in selected molecular contexts, promotes angiogenic signaling, providing a biological rationale for combined vascular endothelial growth factor (VEGF)-targeted and immune checkpoint inhibitor (ICI) therapies, particularly in angiogenic/stromal-high subtypes such as ASPSCR1::TFE3 tumors. Fusion partner identity shapes transcriptional programs, clinical behavior, and therapeutic responsiveness. A distinct inset highlights TFEB-amplified RCC, characterized by increased TFEB copy number within the 6p21 amplicon and frequent co-amplification of VEGFA (±CCND3), driving a highly angiogenic but biologically heterogeneous phenotype that is not obligatorily aligned with the OXPHOS-driven tRCC model. Arrows indicate proposed mechanistic relationships and downstream effects.
September 2, 2026 at 7:37 AM