Glioblastoma recurrence: An NGS-centered seed-soil framework

Recurrence of IDH-wild-type glioblastoma (GBM) remains the major obstacle to improving patient survival. Current recurrence models emphasize tumor-intrinsic mechanisms, including therapeutic resistance, cellular plasticity, and clonal evolution, but do not fully explain how residual tumor cells reconstruct recurrent disease after surgery. Here, we propose an NGS-centered seed-soil framework that considers surgical resection as the starting point of recurrence evolution: residual NEU/OPC/NPC-like tumor cells represent potential recurrence "seed", the postsurgical brain constitutes a dynamically remodeled "soil", and neuron-glioma synapse (NGS) provides a potential interface between residual tumor cells and neurons of this environment. At the recurrence endpoint, recurrent GBM exhibits enhanced neuronal and NGS-associated characteristics, providing an observable phenotype with which this framework can be evaluated. We then examine the potential processes linking these two states, including therapy-associated NGS remodeling, NGS-associated network reconstruction, and neuronal-like migration, which may contribute to the development of local and distant recurrence. Throughout, established observations are distinguished from hypothesis-driven interpretations and untested predictions. Finally, we discuss critical experimental requirements, including longitudinal post-resection models and NGS-specific perturbation, as well as emerging translational opportunities such as neuromodulation and perioperative intervention. This framework shifts the perspective on GBM recurrence from residual tumor-cell survival alone toward dynamic interactions between residual tumor cells and the postsurgical neural environment.