Dynamic Granulocyte Turnover Inferred From cfDNA Methylation Predicts Immunotherapy Benefit in Liver‐Metastatic Small Cell Lung Cancer: A Prospective Biomarker Study

Liver metastases (LM) in small cell lung cancer (SCLC) are associated with a limited response to immune checkpoint inhibitors (ICIs). In this trial, we evaluated the efficacy of first-line envafolimab plus chemotherapy in SCLC patients with LM and explored potential predictive biomarkers. Patients received envafolimab in combination with chemotherapy for four cycles, followed by envafolimab monotherapy until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). Secondary endpoints included safety, objective response, overall survival, and identification of predictive biomarkers. Whole-exome sequencing (WES), transcriptome sequencing, DNA methylation sequencing, circulating tumor DNA (ctDNA) analysis, and cell-free DNA (cfDNA) methylation sequencing were performed on tumor tissues and peripheral blood samples. The objective response rate (ORR) was 75.9%, the disease control rate (DCR) was 100%, and the median PFS was 4.3 months. Granulocyte turnover and TNFRSF9 expression emerged as key indicators across transcriptomic and epigenomic analyses, and were associated with prognosis and liver dysfunction. cfDNA-based assessment of granulocyte turnover reflected both liver damage and tumor dynamics, suggesting its potential for real-time monitoring. These findings suggest that granulocyte activity may contribute to an immunosuppressive tumor microenvironment and serve as a predictive marker for treatment stratification in SCLC with LM.