Pan-cancer analysis and mechanistic insights of tuft cell-like tumors

Tuft cells are rare, chemosensory epithelial cells present in various tissues, including the respiratory and gastrointestinal tracts. Recent studies have revealed their significant role in cancer biology, particularly through the expression of the transcription factor POU2F3, which serves as a master regulator of tuft cell lineage. In several cancer types, including small cell lung cancer, gastric cancer, and breast cancer, POU2F3 expression defines a distinct molecular subtype termed "tuft cell-like" tumors. These tumors exhibit unique transcriptional programs and altered tumor-immune interactions, contributing to their distinct therapeutic sensitivities. In this review, we first analyze the expression patterns of POU2F3 across cancer types using the TCGA and GTEx datasets, revealing differential expression profiles and supporting the classification of tuft cell-like subtypes. We further explore cancer-type-specific signaling pathways regulating tuft cell differentiation and function, such as IL-25, acetylcholine, and taste receptor-related pathways. Finally, we propose that tuft cell-like signatures may serve as promising biomarkers for diagnosis, prognosis, and treatment stratification. Understanding the tuft cell-like–POU2F3 axis could open new avenues for targeted therapies in lineage-defined cancers.