Immunotherapy and the novel therapeutic development for small-cell lung cancer

Small-cell lung cancer (SCLC) is broadly classified into limited- (LS) and extensive-stage (ES) disease, with distinct therapeutic approaches and outcomes. Despite high initial response rates, most patients eventually experience disease progression, particularly in the ES setting, where effective treatment options remain limited. For several decades, platinum-etoposide-based chemotherapy has remained the cornerstone of treatment, with modest improvements in overall survival. Recent advances in cancer immunology have led to the incorporation of immune checkpoint inhibitors as the first-line treatment for many cancers, representing the first major therapeutic breakthrough for SCLC. In ES-SCLC, the addition of programmed death-ligand 1 (PD-L1) inhibitors to platinum-etoposide chemotherapy has become the standard first-line approach based on the survival benefits demonstrated in phase III trials. In LS-SCLC, a consolidation PD-L1 inhibitor following definitive chemoradiotherapy has recently emerged as a new standard, as highlighted by the ADRIATIC trial, which demonstrated a significant survival advantage with durvalumab. Despite these advances, the prognosis of ES-SCLC remains poor with limited response durability and lack of robust predictive biomarkers. Tumor heterogeneity, dynamic phenotypic plasticity, and the absence of actionable genomic alterations continue to hinder precision treatment strategies. In relapse settings, novel antibody-based therapies have begun to reshape the therapeutic landscape. Delta-like ligand 3 (DLL3)-targeted T-cell engagers and antibody-drug conjugates directed against DLL3 and B7-H3 have shown encouraging antitumor activity in heavily pretreated patients, with some agents advancing to late-phase clinical evaluations. This review summarizes the systemic therapies for SCLC, focusing on recent advances in immunotherapy and emerging antibody-based strategies. This review discusses current challenges, including treatment resistance, toxicity, and biomarker development, and highlights future perspectives aimed at enabling more personalized and effective therapeutic approaches for patients with this historically aggressive disease.