Tumor-Infiltrating Mast Cells Enhance Neoadjuvant Therapy Efficacy in ESCC via Modulation of the Desmoplastic Microenvironment

Xing Cui,1,* Xiangmei Zhang,2,3,* Qi Zhao,1 Xin Chen,1,3 Ming He,1,3 Meng Zhang,4 Ruiling Yang,5 Jidong Zhao,1,3 Junfeng Liu1 1Department of Thoracic Surgery, Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, People’s Republic of China; 2Cancer Institute of Hebei Province, Fourth Hospital of Hebei Medical University, Shijiazhuang, 050011, People’s Republic of China; 3Hebei Provincial Key Laboratory of Tumor Microenvironment and Drug Resistance, Hebei Medical University, Shijiazhuang, 050017, People’s Republic of China; 4Department of Clinical Lab, Affiliated Hospital of Hebei University, Baoding, 071000, People’s Republic of China; 5Department of Breast Surgery, Handan Central Hospital, Handan, Hebei, 056000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jidong Zhao, Email ud1291@126.com Junfeng Liu, Email 18939111700@189.cnObjective: Neoadjuvant therapy is essential for locally advanced esophageal squamous cell carcinoma (ESCC), but its efficacy requires improvement. This study investigated the role of tumor-infiltrating mast cells (MCs) in treatment response and prognosis.Methods: An integrated approach was employed, combining single-cell RNA sequencing of paired specimens from one ESCC patient pre- and post-neoadjuvant therapy, immunofluorescence analysis of a retrospective cohort of 68 treatment-naïve ESCC surgical specimens, bioinformatics analysis of public datasets, and in vitro mast cell activation assays.Results: Single-cell sequencing revealed a post-therapy increase in the proportion of MCs among immune cells (4% to 12%), alongside an enriched inflammatory gene profile. In the cohort of 68 patients, higher MC density was associated with smaller tumor diameter (Pearson r = − 0.32, p=0.007) and significantly better overall survival (36 vs 23.5 months, p=0.038). No such correlations were found for macrophages or CD8+ T cells. Bioinformatic analysis linked MCs to extracellular matrix and vascular smooth ...