Revisiting diffuse gliomas in the era of precision medicine: Molecular insights and therapeutic implications

Diffuse gliomas are aggressive and lethal tumors of the Central Nervous System characterized by high molecular complexity and heterogeneity, infiltrative growth and resistance to therapy. The advent of Next-Generation Sequencing integrated molecular profiling strongly redesigned glioma classification, diagnosis and clinical management following the 2021 World Health Organization guidelines. Key molecular alterations, including IDH mutations, 1p/19q co-deletion, ATRX loss, EGFR amplification, TERT promoter mutations and chromosomal abnormalities define distinct oncotypes with prognostic and therapeutic relevance. Despite these advances, clinical outcomes remain often poor due to intrinsic tumor plasticity, persistence of glioma stem-cells and resistance mechanisms driven by the tumor microenvironment, DNA damage response and epigenetic reprogramming. This review provides a comprehensive overview of diffuse gliomas in the era of precision medicine, focusing on molecular reclassification, pathogenesis, therapeutic strategies and resistance mechanisms. Emphasis is placed on advanced diagnostic methodologies, including Next-generation Sequencing, liquid biopsy and new interventions to overcome the restrictive nature of BBB. These approaches represent advancing tools for molecular profiling, disease monitoring, therapy efficacy improvement and early detection of recurrence and enable more personalized management of patients with glioma.