The electrical life of cancer: cancer neuroscience from circuits to patient care.

Abstract

Purpose of review: Cancer neuroscience has evolved from a predominantly preclinical, mechanistic discipline into a clinically relevant framework for understanding and treating patients with brain malignancies. This review synthesizes recent advances across glioblastoma (GBM), diffuse midline glioma (DMG), and brain metastases, with particular emphasis on identifying circuit-level, neurotransmitter-mediated, electrophysiologic, and network properties that are emerging as clinically actionable biomarkers and therapeutic targets.

Recent findings: Human connectomics and retrograde tracing studies demonstrate that GBM integrates into distributed, brain-wide neural circuits. In DMG, neuron-tumor signaling has expanded beyond glutamatergic mechanisms to include GABAergic and cholinergic neurotransmission, while patterns of neural connectivity have been associated with regional immunosuppression and patient survival. Patch-seq and electrophysiologic profiling have identified distinct functional states of malignant cells, and spatial transcriptomic analyses have linked malignant cell plasticity to neuron-rich invasive niches. Although these discoveries are driving the development of neurophysiologic biomarkers and circuit-directed therapeutic strategies, they have not yet translated into clinical practice. Emerging cellular atlases and mechanistic studies of small cell lung cancer and brain metastases further suggest that neural circuit integration is a broader feature of cancer biology rather than a phenomenon restricted to gliomas.

Summary: The field's critical next step is to integrate cancer neuroscience-directed therapeutic strategies with prospectively validated, multimodal biomarkers that account for age and disease-specific neurobiology and reliably distinguish tumor associated states from physiologic aging and adaptive changes within the peritumoral microenvironment.