Crosstalk between cancer-associated fibroblasts and non-neuroendocrine tumor cells in small cell lung cancer involves in glycolysis and antigen-presenting features

Small cell lung cancer (SCLC) is a highly fatal malignancy, the complex tumor microenvironment (TME) is a critical factor affecting SCLC progression. Cancer-associated fibroblasts (CAFs) are crucial components of TME, yet their role in SCLC and the underlying mechanisms during their interaction with SCLC cells remain to be determined. In this study, a co-culture system comprising MRC5 fibroblasts and SCLC cell lines was constructed. RNA sequencing (RNA-seq) was performed on co-cultured and separately cultured MRC5 and H196 cells to identify differentially expressed genes (DEGs) and enriched signaling pathways. We obsertved that non-neuroendocrine (non-NE) SCLC-derived CAFs exhibited more abundance and DEGs than NE SCLC-derived CAFs did. Enriched glycolysis-related genes, increased glucose uptake, and upregulated glycolytic signaling proteins were found in non-NE SCLC cells when interaction with MRC5 fibroblasts, confirming CAF-mediated glycolysis promotion. Additionally, non-NE SCLC cell-educated CAFs exhibited features of antigen-presenting CAFs (apCAFs), as indicated by the expression of major histocompatibility complex (MHC) molecules. This study emphasizes the pro-tumor function of CAFs in SCLC by promoting glycolysis and impairing T cell function, providing direction for the development of novel therapeutic approaches targeting CAF in SCLC.