From Cellular Plasticity to Relapse Competence in Small Cell Lung Cancer: Rethinking the Biology of Recurrence

Small cell lung cancer (SCLC) is characterized by profound initial treatment sensitivity followed by frequent recurrence. Although genetic resistance contributes to disease progression, increasing evidence indicates that SCLC cells can transition among phenotypic states, allowing tumor composition and therapeutic vulnerabilities to evolve during treatment. How cellular plasticity and stem-like properties intersect with treatment persistence and subsequent tumor regeneration, however, remains poorly understood. In this Review, we integrate evidence from SCLC developmental biology, cancer stemness, cellular plasticity, and longitudinal tumor evolution to examine the transition from treatment response to recurrence. We distinguish treatment persistence from relapse competence, defined here as the functional capacity of therapy-surviving cells to regenerate recurrent tumor growth rather than as a discrete cellular subtype. We discuss how genetic selection and non-genetic adaptation shape residual disease, how cell state evolution alters therapeutic vulnerabilities, and how lineage-aware experimental approaches could identify recurrence-driving populations. Understanding the cellular trajectories connecting treatment-naive, residual, and recurrent SCLC may reveal opportunities to therapeutically intercept the evolutionary processes that enable recurrence.