Lineage infidelity in small-cell lung cancer: driving subtype transitions and acquired therapeutic vulnerabilities

Abstract Small-cell lung cancer (SCLC) has long been characterized by its aggressive clinical course and a deceptive initial sensitivity to chemotherapy that almost invariably yields to recalcitrant disease. Recent genomic and transcriptomic profiling has dismantled the historical view of SCLC as a monolithic entity, revealing a complex landscape of inter- and intra-tumoral heterogeneity defined by the differential expression of key transcription factors—ASCL1, NEUROD1, POU2F3, and YAP1. Central to this heterogeneity is the phenomenon of lineage infidelity, a form of cellular plasticity where SCLC cells transit between molecularly distinct states to evade physiological and therapeutic pressures. In this review, we decode the epigenetic and transcriptional networks that govern these subtype transitions, highlighting how the loss of canonical lineage markers drives the emergence of variant phenotypes with altered metabolic and tumor profiles. We argue that this plasticity is not merely a byproduct of tumor evolution but a fundamental engine of chemoresistance. Crucially, we identify the acquired therapeutic vulnerabilities inherent to each state, proposing a transition from broad-spectrum cytotoxic regimens to a trajectory-based precision medicine framework. By targeting the gatekeepers of lineage identity and exploiting the transient weakness of emerging subtypes, we outline a roadmap for overcoming the historical stalemate in SCLC treatment and achieving sustained clinical responses.