Precision modulation of tumor excitability: Targeting cell phenotypic heterogeneity for next‐generation cancer therapy

Electrical excitability, long regarded as a defining property of neurons, is now increasingly recognized in cancer cells, particularly within phenotypically heterogeneous tumor subpopulations. A recent Nature study revealed that the neuroendocrine (NE) subpopulation of small cell lung cancer exhibits neuron‐like excitability, capable of generating action potentials and forming intercellular signaling networks that enhance malignancy and metastasis. This discovery highlights how electrical excitability can arise in cancer cells through metabolic reprogramming and dynamic interactions within the tumor microenvironment. Moreover, heterogeneous tumor subpopulations may cooperate to sustain excitability via metabolic coupling. These findings challenge conventional views of tumor biology, establishing a new paradigm in which cancer heterogeneity drives electrophysiological diversity and functional plasticity, fundamentally reshaping our understanding of tumor behavior, communication, and progression.