Glioma intratumoral heterogeneity remains a critical barrier to effective treatment, driving recurrence and resistance to therapy. Emerging evidence suggests that glioma cells acquire neural-like features through paracrine and synaptic communication with neural cells, fostering functional diversity within tumors. While neuro-cancer interactions are implicated in glioma heterogeneity, their precise roles remain incompletely synthesized. Here, by consolidating these discoveries, a conceptual framework is proposed for understanding the glioma intratumoral heterogeneity shaped by neuro-cancer interactions: cellular phenotypes, spanning neurogliomal synapses, glioma networks, and neuronal-like motility; and transcriptional states, which exhibit remarkable resemblance to neural cells. These diverse cellular phenotypes and transcriptional states synergistically fuel glioma progression, invasion, and resistance. By emphasizing the converging phenotypical and transcriptional evidence with spatial context within them, an underexplored but critical role of neuro-cancer interactions are proposed in glioma intratumoral heterogeneity. This provides potential strategies to explore and disrupt these neuro-cancer interactions, offering new insights to address glioma intratumoral heterogeneity for improved therapeutic outcomes.
Keywords: cancer neuroscience; cellular phenotype; functional adaptation; intratumoral heterogeneity; transcriptional states.
© 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.