Small cell lung cancer: from immunobiological mechanisms to clinical advances

Small cell lung cancer (SCLC) remains one of the most aggressive malignancies, characterized by limited therapeutic options and persistently poor survival outcomes. This review summarizes recent advances in understanding the immunosuppressive tumor microenvironment, emerging therapeutic strategies, and biomarker-driven approaches that may enable more precise treatment. The SCLC microenvironment is dominated by suppressive immune cell populations-including regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells-that collectively inhibit antitumor immune responses. Integrative molecular and immunologic profiling has defined four transcription factor-driven subtypes, each exhibiting distinct immune phenotypes and differential responses to therapy. Although current immunotherapies have conferred meaningful yet modest clinical gains, combining PD-1/PD-L1 blockade with chemotherapy has improved survival in extensive-stage disease, and CTLA-4 inhibition demonstrates potential within combination regimens. Beyond immune checkpoint blockade, novel therapeutic modalities such as DLL3-targeted antibody-drug conjugates, bispecific T-cell engagers, and emerging B7-H3-directed strategies have shown encouraging activity in treatment-refractory settings. However, conventional biomarkers-including PD-L1 expression and tumor mutational burden-remain unreliable in SCLC, and the mechanisms underlying therapeutic resistance are still insufficiently understood. Future efforts should prioritize the refinement of molecular subtyping frameworks, the establishment of robust biomarker-guided patient stratification, the elucidation of resistance pathways, and the development of precision immunotherapies tailored to SCLC heterogeneity.