Single-cell RNA sequencing reveals cellular and molecular heterogeneity in extensive-stage small cell lung cancer with different chemotherapy responses

Despite its rapid growth and early metastasis, small cell lung cancer (SCLC) is more chemosensitive than other lung cancers. However, some patients with extensive-stage SCLC (ES-SCLC) do not respond to first-line chemotherapy, resulting in poorer prognoses due to inter- and intratumoral heterogeneity. In this study, we conducted single-cell RNA sequencing of 9 treatment-naive ES-SCLC samples. Based on comprehensive imaging evidence collected before and after two cycles of first-line chemotherapy and sample types, the 9 samples were categorized into three groups: progressive disease with the pleural effusion sample (PD_PE group, n = 1), progressive disease with the primary tumor samples (PD_TU group, n = 2), and partial response with the primary tumor samples (PR_TU group, n = 6). Based on transcriptomic landscape and cell type composition, the PD samples represent a multicellular ecosystem distinct from PR samples. The immune response, along with the elevated expression of immune-related genes such as LTF, SLPI, SPARC and IGLV1-51, might correlate with a poor first-line chemotherapy response in ES-SCLC. We also observed that T cells, particularly effector T cells, were more abundant in PD_TU group, with TNFA signaling via NFκB being significantly enriched. The PD_TU group was strongly enriched with macrophages and tumor-associated macrophages (TAMs), and angiogenesis in TAMs was highly enriched. Immunomodulatory fibroblasts were highly abundant in PD_TU group, and the pathways of epithelial-mesenchymal transition and angiogenesis were upregulated. This study offers the first comprehensive insights into the cellular and molecular heterogeneity in treatment-naive patients with ES-SCLC with different chemotherapy responses.