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By integrating multiple cohorts, we found that high tumor\u2010intrinsic ICOSLG was associated with poor overall survival (OS) in the TU\u2010SCLC cohort (\n                    <jats:italic>p<\/jats:italic>\n                    \u00a0=\u00a00.010) and the Wang et\u00a0al. cohort (\n                    <jats:italic>p<\/jats:italic>\n                    \u00a0&lt;\u00a00.001), and was associated with inferior efficacy to chemo\u2010immunotherapy (hazard ratio [HR]\u00a0=\u00a02.66,\n                    <jats:italic>p<\/jats:italic>\n                    \u00a0=\u00a00.008). Consistently, the ICOSLG high subgroup exhibited significantly reduced functional CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell infiltration, elevated exhausted CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells, decreased effector molecules such as GZMK and IFNG, and enrichment of malignant pathways, including hypoxia, epithelial\u2013mesenchymal transition, and others. Meanwhile, the correlation between ICOSLG and NEUROD1 expression was observed. On the contrary the subgroup high in ICOS,\u00a0the main ICOSLG receptor, harbored NOTCH pathway mutations, showed an inflamed tumor microenvironment, better prognosis, and prolonged OS with chemo\u2010immunotherapy (HR\u00a0=\u00a00.52,\n                    <jats:italic>p<\/jats:italic>\n                    \u00a0=\u00a00.003). Dual ICOSLG and ICOS stratification revealed that the ICOSLG low and ICOS high subgroup derived the greatest benefit from chemo\u2010immunotherapy (median OS: 17.2\u00a0vs. 9.8 months;\n                    <jats:italic>p<\/jats:italic>\n                    \u00a0&lt;\u00a00.001). Collectively, this dual\u2010stratification strategy refined patient selection for chemo\u2010immunotherapy, unveiled actionable targets, and ultimately advanced precision immunotherapy in SCLC.\n                  <\/jats:p>","DOI":"10.1002\/mco2.70782","type":"journal-article","created":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T01:35:02Z","timestamp":1780018502000},"source":"Crossref","is-referenced-by-count":0,"title":["Inducible T Cell Costimulator Ligand and Inducible T Cell Costimulator Stratification Identify Dichotomous Tumor Microenvironment and Guide Chemo\u2010Immunotherapy in Small Cell Lung Cancer"],"prefix":"10.1002","volume":"7","author":[{"given":"Qiji","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Thoracic Surgery Shanghai Pulmonary Hospital School of Medicine Tongji University  Shanghai 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