Cracking the Code of Immunotherapy Resistance in SCLC: Molecular Insights and Emerging Solutions

Small cell lung cancer (SCLC) is an aggressive neuroendocrine malignancy with dismal prognosis. Although immune checkpoint inhibitors (ICIs) have revolutionized non-small cell lung cancer, their impact in SCLC has been modest, with only 2-3 months improvement in median survival. This paradox persists despite SCLC's high tumor mutational burden, suggesting complex, multifactorial resistance mechanisms. Here we critically review the latest advances in understanding immunotherapy resistance in SCLC. We highlight tumor-intrinsic immune escape mechanisms, including genetic drivers, MHC class I downregulation and epigenetic repression, as well as the profoundly immunosuppressive tumor microenvironment. We also examine the evolving classification of SCLC into molecular subtypes, which reveals distinct immunogenic landscapes with potential predictive value for immunotherapy response. Importantly, we integrate a comprehensive update on ongoing and recently reported clinical trials that aim to restore immune responsiveness, ranging from combination ICI regimens to novel strategies involving epigenetic modulators, antigen presenting pathway agonists, and bispecific T-cell engagers. Finally, we discuss translational strategies to overcome immunotherapy resistance and outline a precision immunotherapy roadmap, arguing for biomarker-guided and subtype-stratified clinical trial design. By synthesizing mechanistic, translational, and clinical perspectives, this review provides a framework for rational therapeutic innovation in SCLC.