POU2F3 is a transcription factor that functions as a master regulator of cell-type-specific differentiation through binding to octamer DNA motifs 1. In normal physiology, POU2F3 drives tuft cell identity—rare chemosensory cells coordinating immune and neural responses in mucosal tissues—through formation of a complex with coactivator proteins OCA-T1 and OCA-T2 1. POU2F3 also regulates keratinocyte differentiation pathways. Clinically, POU2F3 is most significant as a defining marker of SCLC-P, a distinct small cell lung cancer subtype characterized by low/negative neuroendocrine marker expression 23. SCLC-P tumors represent approximately 7-13% of SCLC cases and exhibit unique biological properties, including fewer TP53 and RB1 mutations compared to other SCLC subtypes 4. The POU2F3-OCA-T complex constitutes a molecular vulnerability of tuft-cell-like small cell lung cancer 1. POU2F3 demonstrates 82.1% sensitivity and 99.4% specificity for diagnosing neuroendocrine-low SCLC, making it a highly accurate diagnostic marker 4. Understanding POU2F3-defined SCLC subtypes may enable subtype-matched therapeutic strategies, though clinical vulnerabilities specific to SCLC-P remain incompletely characterized.