Clinical efficacy and biomarkers of neoadjuvant chemoimmunotherapy in locally advanced esophageal squamous cell carcinoma

Background: Neoadjuvant immunotherapy has emerged as a promising strategy for esophageal squamous cell carcinoma (ESCC). This study evaluates the therapeutic efficacy and safety of neoadjuvant immunochemotherapy (nICT) in ESCC and explores potential biomarkers associated with treatment outcomes. Methods: Patients with locally advanced ESCC were enrolled and received two cycles of nICT followed by surgical resection. The primary endpoint was the pathological complete response (pCR) rate, while secondary endpoints included overall survival (OS), event-free survival (EFS), safety, and the identification of predictive biomarkers. Results: A total of 47 patients were enrolled in the study, with 42 undergoing surgical 40 resection, all of whom achieved R0 resection. The rates of complete and partial pathological responses were 28.5% and 16.7%, respectively. The 1-year and 2-year EFS rates were 82% and 37.3%, while OS rates reached 100% and 71.4%, respectively. The majority of treatment-related adverse events (TRAEs) were Grade 1–2, and no surgical delays were observed. RNA sequencing analysis revealed epithelial-mesenchymal transition (EMT) as the most significantly enriched pathway in non-responders. Notably, higher infiltration of normal fibroblasts (NF) correlated with improved pathological response and enhanced long-term survival, whereas myofibroblastic cancer-associated fibroblasts (myCAF) negatively influenced treatment efficacy and clinical outcomes. Conclusions: Neoadjuvant PD-1 inhibitors combined with chemotherapy demonstrate encouraging potential for patients with locally advanced ESCC, inducing a robust immune response that correlates with clinical outcomes. The infiltration of myCAF emerges as a potential predictive biomarker for treatment response and disease progression, highlighting the need for further mechanistic exploration and validation in larger cohorts. Trial registration: NCT, NCT05028231. Registered 24 August 2021