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Background: Esophageal squamous cell carcinoma (ESCC) is the predominant subtype of esophageal cancer, with poor outcomes following neoadjuvant chemoradiotherapy (NCRT). Neoadjuvant chemoimmunotherapy (NCIT) has emerged as a promising strategy, but reliable predictive biomarkers remain lacking. This study aimed to develop an AI-driven pathomic model for NCIT response prediction and explore its biological mechanisms. Methods: We analyzed 269 H&E-stained whole-slide images (WSIs) from 198 ESCC patients (104 from Tongji Hospital, 94 from TCGA). Using ResNet152, we segmented WSIs into four tissue categories (tumor cells, stroma, lymphocytes, and necrosis), extracted spatially weighted pathomic features, and constructed the ECiT score via logistic regression. An integrated model combining the ECiT score with clinical variables (T stage, P53 status) was developed. Mechanistic analyses were performed using TCGA-ESCA and GSE160269 datasets. Results: The integrated model achieved AUCs of 0.897 (training) and 0.809 (temporal validation), outperforming clinical (AUC = 0.624) and pathomic-only (AUC = 0.751) models. Mechanistically, a high ECiT score correlated with enhanced immune activation (elevated CD4⁺ memory T cell infiltration), while low scores were linked to endoplasmic reticulum (ER) stress-unfolded protein response (UPR) activation. EIF2S3 was identified as a key molecular mediator, correlating with three pathomic features, UPR activation, and poor prognosis. Conclusions: This study may offer a preliminary indicator that could assist in personalized clinical decision-making. Correlative evidence suggests that the EIF2S3-mediated ER stress-UPR axis represents a potential candidate therapeutic target to overcome NCIT resistance, generating testable hypotheses to advance precision oncology for resectable locally advanced ESCC.