Neurodevelopmental Blueprint in Gliomas: Toward an Ontogenetic Multimodal Integrated Therapy

Neuroepithelial tumors, including diffuse gliomas and embryonal neoplasms, remain among the most lethal cancers despite major advances in molecular diagnostics and some novel targeted therapies for subsets of patients. A persistent barrier to progress is the lack of a unifying framework that integrates their cellular hierarchy, spatial heterogeneity, and distinctive patterns of progression. In this review, we synthesize converging evidence that neuroepithelial tumor biology represents a pathologic re-enactment of brain ontogeny. Integrating molecular, single-cell, histoarchitectonic, and anatomic observations, we propose that neoplastic transformation, aberrant lineage commitment, and dedifferentiation mirror and invert physiological ontogenetic trajectories. This ontogenetic logic provides a coherent explanation for key hallmarks of neuroepithelial tumors, including intratumoral mosaicism, directional anatomic spread, and the emergence of therapy-resistant tumor-propagating cell states. Ontogenetic multimodal integrated therapy is an anatomy-guided strategy that aligns neurosurgery, radiotherapy, and pharmacotherapy with tumor stage and ontogenetic architecture. By shifting emphasis from radiologically visible tumor bulk to compartment-based developmental logic, this framework offers testable hypotheses and a clinically oriented paradigm for diagnosis, treatment planning, and longitudinal monitoring in patients with neuroepithelial tumors.