Pathological Pathways of Olfactory Neuroblastoma: From Molecular Mechanisms to Targeted Therapy: A Narrative Review

Olfactory neuroblastoma (ONB), also known as esthesioneuroblastoma, is a rare malignant tumor arising from the olfactory epithelium of the sinonasal tract. Surgery combined with radiotherapy remains the standard treatment for localized disease, whereas chemotherapy is mainly used in advanced or recurrent cases. However, recurrent and metastatic ONB continues to present major therapeutic challenges, and traditional staging and histological grading systems cannot fully explain the marked differences in clinical behavior among patients. The primary objective of this review is to summarize recent advances in the molecular pathology, tumor microenvironment (TME), and emerging targeted therapeutic strategies in ONB. Emerging genomic and transcriptomic studies suggest that ONB comprises biologically heterogeneous tumors with distinct molecular and transcriptional programs associated with proliferation, neuroendocrine differentiation, angiogenesis, and stromal remodeling. Furthermore, we explore the increasing attention directed toward the TME, including immune-cell infiltration, angiogenic signaling, and immune checkpoint expression, which may influence therapeutic response. These molecular findings have generated interest in several potential targeted treatment strategies, including peptide receptor radionuclide therapy (PRRT), anti-angiogenic therapy, epigenetic-targeted therapy, immunotherapy, and DNA-damage-response-targeted approaches. Ultimately, although the current evidence remains limited because of the rarity of the disease, novel therapeutic strategies for ONB are emerging. In addition to summarizing the current landscape, this review discusses the translational challenges and future directions for precision oncology and biomarker-driven therapy, aiming to provide insights for improving individualized patient management.