Yang Bo, Chen Ruiji, Zu Mali, Yao Jie, Ren Hong, Lin Yingxue, Zhang Bo, Ji Tianjiao, Liu Yang
Department of Thoracic Surgery, The First Medical Center of the People Liberty Army General Hospital, Beijing, China.
Postgraduate School, Medical School of Chinese People Liberty Army, Beijing, China.
Front Cell Dev Biol. 2025 Jul 23;13:1613296. doi: 10.3389/fcell.2025.1613296. eCollection 2025.
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.
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 .
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-associated gene upregulation (e.g., ) and immunosuppressive pathways. Meta-Programs (MPs) analysis identified a hypoxia-driven fibroblast state (MP5) containing that correlated with treatment resistance. experiments, co-localized with α-SMA + fibroblasts and directly induced PD-L1 expression in tumor cells, linking CAFs secreted to immunosuppressive PD-L1 upregulation.
This cross-cancer single-cell atlas reveals S100A4, secreted by CAFs, as a conserved mediator of PD-L1 upregulation in tumor cells, driving immunosuppression and resistance to nICT. The atlas and mechanistic findings provide a rationale for targeting S100A4 to enhance treatment efficacy, pending validation in larger cohorts and mechanistic studies. This resource also supports the development of personalized, cross-cancer neoadjuvant strategies.
新辅助治疗（NAT）通过改善手术效果和生存率改变了癌症治疗方式，但多种癌症类型的耐药机制仍不清楚。本研究旨在利用跨癌症单细胞测序数据解读新辅助治疗期间肿瘤生态系统动态，重点识别免疫抑制和治疗耐药的关键介质。
整合来自五种实体瘤（食管鳞状细胞癌、食管胃交界癌、结直肠癌、宫颈癌和三阴性乳腺癌）的单细胞RNA测序（scRNA-seq）数据集。对这五种癌症类型的数据进行严格处理，以标准化所有数据集中的细胞类型。进行细胞间通讯分析、通过非负矩阵分解的元程序（MPs）分析以及功能富集分析。免疫组织化学（IHC）和蛋白质印迹法验证了S100A4的表达和PD-L1的诱导。
我们构建了跨癌症类型的单细胞图谱，并系统地描述了新辅助治疗后肿瘤细胞和不同微环境细胞群体的动态变化，以及它们的基因表达和通路改变。我们的研究结果强调，癌症相关成纤维细胞（CAFs）与肿瘤细胞之间的串扰是新辅助治疗耐药的关键决定因素。成纤维细胞在治疗后经历了显著的状态转变，其特征是缺氧相关基因上调（如 ）和免疫抑制通路。元程序（MPs）分析确定了一种由缺氧驱动的成纤维细胞状态（MP5），其中包含 ，与治疗耐药相关。 实验表明， 与α-SMA+成纤维细胞共定位，并直接诱导肿瘤细胞中PD-L1的表达，将CAFs分泌的 与免疫抑制性PD-L1上调联系起来。
这一跨癌症单细胞图谱揭示了CAFs分泌的S100A4是肿瘤细胞中PD-L1上调的保守介质，驱动免疫抑制和对新辅助诱导化疗（nICT）的耐药。该图谱和机制研究结果为靶向S100A4以提高治疗效果提供了理论依据，有待在更大队列和机制研究中进行验证。该资源还支持个性化、跨癌症新辅助策略的开发。
