Inducible T Cell Costimulator Ligand and Inducible T Cell Costimulator Stratification Identify Dichotomous Tumor Microenvironment and Guide Chemo-Immunotherapy in Small Cell Lung Cancer.

Inducible T cell costimulator ligand (ICOSLG) regulates T cell functional states, yet its role in small cell lung cancer (SCLC) remains poorly characterized. By integrating multiple cohorts, we found that high tumor-intrinsic ICOSLG was associated with poor overall survival (OS) in the TU-SCLC cohort (p = 0.010) and the Wang et al. cohort (p < 0.001), and was associated with inferior efficacy to chemo-immunotherapy (hazard ratio [HR] = 2.66, p = 0.008). Consistently, the ICOSLG high subgroup exhibited significantly reduced functional CD8+ T cell infiltration, elevated exhausted CD8+ T cells, decreased effector molecules such as GZMK and IFNG, and enrichment of malignant pathways, including hypoxia, epithelial-mesenchymal transition, and others. Meanwhile, the correlation between ICOSLG and NEUROD1 expression was observed. On the contrary the subgroup high in ICOS, the main ICOSLG receptor, harbored NOTCH pathway mutations, showed an inflamed tumor microenvironment, better prognosis, and prolonged OS with chemo-immunotherapy (HR = 0.52, p = 0.003). Dual ICOSLG and ICOS stratification revealed that the ICOSLG low and ICOS high subgroup derived the greatest benefit from chemo-immunotherapy (median OS: 17.2 vs. 9.8 months; p < 0.001). Collectively, this dual-stratification strategy refined patient selection for chemo-immunotherapy, unveiled actionable targets, and ultimately advanced precision immunotherapy in SCLC.