Novel insights into retinoblastoma: From oncogenic circuitry to precision diagnosis and eye-preserving therapies

Retinoblastoma (RB) represents the most common primary intraocular malignancy in childhood and stands as a paradigm for translating molecular oncology into precision clinical management. This review synthesizes the comprehensive evolution in the understanding and treatment of RB. First, we deconstruct the intricate oncogenic circuitry that extends far beyond Knudson's classic "two-hit" RB1 inactivation model, describing non-classical MYCN-driven pathogenesis, multi-layered epigenetic reprogramming (including chromatin, RNA and histone changes), and distinct histological subtypes with defined clinical correlates, such as the favorable-prognosis cavitary RB. Single-cell genomics has elucidated the cellular origin from cone precursor cells and intratumoral heterogeneity. Risk stratification has been refined through well-defined classification systems, from the therapy-guiding International Intraocular Retinoblastoma Classification (IIRC) to the comprehensive American Joint Committee on Cancer Tumor-Node-metastasis (AJCC TNM) staging. Furthermore, the diagnostic paradigm has advanced from conventional anatomical imaging to liquid biopsies, enabling non-invasive molecular staging and monitoring via tumor-derived cell-free DNA analysis. Concurrently, the therapeutic landscape has undergone a radical shift, moving from enucleation and external-beam radiotherapy to an era dominated by local sight-preserving strategies. We provide a critical synthesis of the evidence for intravenous chemotherapy and the transformative role of super-selective intra-arterial chemotherapy (IAC), and describe essential randomized controlled trials, technical innovations, and optimized drug regimens. Finally, we explore emerging targeted molecular therapies and future directions. By integrating cutting-edge molecular insights with robust, high-level clinical evidence, this review offers the framework for achieving patient and eye survival as well as vision preservation in children with Retinoblastoma.