INTRODUCTION: Digestive system pan-cancer is one of the lethal malignant tumors, which have the propensity for poor prognosis and difficult treatment. Endoplasmic reticulum (ER) stress has served as a pivotal role in the progression of the tumor, while the implication of ER stress on digestive system pan-cancers still needs elucidation, especially from the perspective of clinical outcome and that of genomic features. METHODS: First, Among the ER STRESS factors from the REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR (113 genes) and HALLMARK_UNFOLDED_PROTEIN_RESPONSE (92 genes) terms, 153 ER STRESS regulators were identified after removing replicates. The somatic mutation data and copy number variation data of gastrointestinal pan-cancer were downloaded from The Cancer Genome Atlas (TCGA) database. Then, we explored the clinical outcome and genetic mutation of ER stress-related differentially expressed genes (DEGs) by multiple bioinformatics analysis. Subsequently, we analyzed the Spearman correlation between the drug sensitivity of 179 gastrointestinal anticancer drugs and the transcriptional expression of 153 ER stress factors in 769 cancer cell lines of the GDSC2 cohort. Next, ssGSEA method was used to quantify the immune cell infiltration scores in the tumor microenvironment, and Spearman correlation was used to calculate the correlation between ER stress scores and immune cell infiltration. Finally, we analyzed the cellular origin of ER stress factor dysregulation. RESULTS: We analyzed the genomic changes and clinical outcomes of ER stress factors in different tumors of gastrointestinal pan-cancer. Endoplasmic reticulum stress factor (ER) in digestive tract tumors showed high SNV mutation frequency, less methylation dysregulation and was associated with multiple oncogenic pathways. Endoplasmic reticulum stress factor (ER) is a risk factor for many cancers, but the effect on overall survival in rectal adenocarcinoma is opposite to that in other gastrointestinal tumors. And ER stress factors are highly correlated with drugs that target important pathways. DISCUSSION: Based on the clinical prognosis and genomic analysis of ER stress-related factors in patients with gastrointestinal pan-cancer, this study provides a new direction for further research on gastrointestinal pan-cancer.