Immunotherapy Resistance in Small Cell Lung Cancer: Mechanisms and Therapeutic Vulnerabilities

In small cell lung cancer (SCLC), immune checkpoint inhibitors (ICIs) combined with platinum-based chemotherapy are standard first-line treatment for extensive-stage disease. However, durable disease control remains uncommon. This review examines lineage plasticity, epigenetic regulation, defective antigen presentation, and altered DNA sensing and interferon responses. These processes interact with T-cell dysfunction, suppressive myeloid populations, and organ-specific niches. Treatment-associated clonal and cell-state changes complicate the distinction between chemotherapy resistance and immune escape. We relate these processes to primary and acquired resistance and assess interventions according to treatment setting and evidence source. Randomized SCLC trials support selected maintenance and first-line combination regimens and delta-like ligand 3 (DLL3)-directed T-cell redirection. By contrast, evidence for epigenetic, innate-immune, and myeloid targeting remains largely preclinical. Findings from non-small cell lung cancer (NSCLC) and other tumors provide indirect evidence that cannot be extrapolated directly to SCLC. Emerging lineage vulnerabilities and traditional Chinese medicine remain exploratory. We discuss the overlap between chemotherapy and immunotherapy resistance, opportunities and constraints arising from plasticity, and the validation needed for mechanism-informed interventions.