Deciphering the tumor ecosystem dynamics undergoing immunochemotherapy therapy across multiple cancer types unveils the immunosuppressive role of S100A4 in fibroblasts by promoting PD-L1 expression in tumor cells

作者：Bo Yang, Ruiji Chen, Mali Zu, Jie Yao, Hong Ren, Yingxue Lin, Bo Zhang, Tianjiao Ji, Yang Liu · 发表于：Frontiers in Cell and Developmental Biology · 年份：2025 · DOI：10.3389/fcell.2025.1613296 · 被引用次数：2 · 研究领域：Single-cell and spatial transcriptomics、Cancer Cells and Metastasis、Cancer Genomics and Diagnostics

Background Neoadjuvant therapy (NAT) has transformed cancer treatment by improving surgical outcomes and survival rates, yet resistance mechanisms across multiple cancer types remain unclear. This study aimed to decipher tumor ecosystem dynamics during NAT using cross-cancer single-cell sequencing data, focusing on identifying key mediators of immunosuppression and treatment resistance. Methods Single-cell RNA-sequencing (scRNA-seq) datasets from five solid tumors (esophageal squamous cell carcinoma, esophagogastric junction carcinoma, colorectal cancer, cervical cancer, and triple-negative breast cancer) were integrated. The data from these five cancer types underwent a rigorous process to standardize cell types across all datasets. Cell-cell communication analysis, Meta-Programs (MPs) via non-negative matrix factorization, and functional enrichment were performed. Immunohistochemistry (IHC) and Western blot validated S100A4 expression and PD-L1 induction in vitro . Results We constructed a single-cell map across cancer types and systematically characterized dynamic changes in tumor cells and diverse microenvironmental cell populations following neoadjuvant therapy, along with thier gene expression and pathway alterations. Our findings highlight that crosstalk between cancer-associated fibroblasts (CAFs) and tumor cells represents a critical determinant of neoadjuvant therapy resistance. Fibroblasts underwent significant state transitions post-treatment, marked by hypoxia-as...