The Complex Biology of EIF3E (int6): From Its Original Discovery to EIF3E::RSPO2 Fusions in Solid Tumors and Lymphoma Susceptibility

Over the past three decades, the biology of EIF3E (int6) has emerged as far more complex than originally anticipated. Initially identified as a common integration site of Mouse Mammary Tumor Virus (MMTV) and subsequently recognized as a component of the eukaryotic translation initiation factor 3 (eIF3) complex, EIF3E is now understood as a multifunctional regulator involved in selective mRNA translation, proteostasis, genome stability, cellular stress responses, and tissue homeostasis. Recent studies have further extended this framework by demonstrating that conditional Eif3e deficiency promotes lymphoma susceptibility in mice, providing in vivo evidence linking EIF3E-dependent translational regulation to immune homeostasis and cancer development. This focused review retraces the scientific journey of EIF3E from its discovery as int6 to the progressive definition of its diverse biological functions and context-dependent roles in cancer. Particular attention is given to the historical relationship between int6 (EIF3E) and int7 (RSPO2), whose unexpected reunion in recurrent EIF3E::RSPO2 fusions in human solid tumors provides a unique bridge between classical retroviral insertional mutagenesis and contemporary cancer genomics. While transcriptional activation of RSPO2 through EIF3E regulatory elements represents the established oncogenic mechanism of the fusion, whether disruption of one EIF3E allele exerts additional biological effects remains unknown. Together, these observations highlight EIF3E as a nexus between selective translation, cellular homeostasis, and cancer, while emerging links between epigenomic, epitranscriptomic, and translational regulation open new perspectives for understanding its context-dependent functions in tumorigenesis.