Emerging Therapeutic Strategies in Small-Cell Lung Cancer: From Adaptive Resistance to Precision Therapy

Background/Objectives: Small-cell lung cancer (SCLC) remains one of the most therapeutically challenging malignancies despite recent advances in chemoimmunotherapy. Although platinum–etoposide combined with programmed death ligand 1 (PD-L1) blockade has modestly improved survival in extensive-stage disease, most patients ultimately develop treatment resistance. This review examines the evolving biological basis of therapeutic resistance and discusses how emerging treatment strategies may be integrated into biologically informed clinical development. Methods: We conducted a narrative review of recent translational studies, clinical trials, regulatory updates, and major oncology meeting presentations addressing emerging therapeutic strategies, biomarkers, and adaptive resistance mechanisms in SCLC. Results: Advances in molecular profiling have established that SCLC comprises dynamically evolving transcriptional states characterized by lineage plasticity, replication-stress dependency, immune suppression, and antigen remodeling. These biological insights have accelerated the development of delta-like ligand 3 (DLL3)-directed immune-redirection strategies, next-generation antibody–drug conjugates, DNA damage response-targeting therapies, and epigenetic approaches. Across these platforms, however, clinical translation remains constrained by antigen heterogeneity, biomarker instability, lineage plasticity, immune dysfunction, and cumulative toxicity. We organize the available evidence across three clinically relevant treatment windows—induction, post-induction residual disease, and relapse—to clarify how therapeutic timing may influence the role and expected clinical performance of each strategy. Conclusions: Future clinical development should prioritize the prospective validation of dynamic biomarkers and treatment strategies tailored to specific disease stages. Such an approach may improve patient selection, guide therapeutic sequencing, and increase the durability of treatment benefit in extensive-stage SCLC.