Junlei Han, Fanwei Meng, Jiemeng Ding, Jun Chen, Li Wang, Chaoyang Shi
ABSTRACT The nervous system is emerging as a central regulator of tumor initiation, progression, and therapeutic response. However, the dynamic mechanisms linking neural activity to malignant, immune, and barrier states remain difficult to dissect in vivo. Animal models capture key aspects of cancer neuroscience, but poorly control human‐specific multicellular interfaces, neural activity, secreted signals, and real‐time readouts. AI‐enabled organoid chip platforms offer a complementary route to reconstruct and interrogate the nerve‐tumor interface by integrating human‐derived organoids, microfluidic control, sensing, and computational modeling. Here we review advances in nerve‐tumor organoids and integrate relevant progress in microfluidics, in situ functional sensing, and AI‐driven modeling. These systems can enable controlled studies of perineural invasion, nerve‐mediated immune regulation, trans‐barrier drug responses, and longitudinal functional states. Key challenges include model standardization, long‐term stability, multimodal data interpretation, and clinical translation. AI‐enabled organoid chip platforms could help shift cancer neuroscience from descriptive observation towards perturbable, human‐relevant and data‐rich systems for mechanism discovery and precision therapy assessment.