Molecular and immune heterogeneity across limited-stage and extensive-stage small cell lung cancer

Immune checkpoint inhibitors are now standard care for small-cell lung cancer (SCLC); however, a profound prognostic disparity persists between limited-stage (LS) and extensive-stage (ES) disease. Although clinical staging defines tumor spread, the specific molecular characteristics distinguishing LS from ES remain poorly understood, despite their potential link to immunotherapy responsiveness. To investigate this, we profiled transcriptomes of 361 patients with histologically confirmed SCLC (100 LS-SCLC and 261 ES-SCLC). Analysis identified distinct stage-specific features: LS tumors exhibit enriched immune signatures, notably B cell-receptor signaling, whereas ES tumors are defined by upregulated MYC targets and oxidative phosphorylation. A derived ‘pseudostage rank’ captured this transcriptomic continuum, effectively stratifying patients. Notably, patients with high rank ES showed significantly worse survival with chemoimmunotherapy (median difference: 5.8 months, P < 0.05), a distinction absent in chemotherapy-only cohorts. These findings suggest that the molecular transition from LS to ES involves metabolic reprogramming and immune evasion. Consequently, these molecular subtypes and pseudostage ranking offer novel biomarkers for therapeutic stratification, moving beyond conventional clinical staging.