Towards a pan-cancer atlas of endoplasmic reticulum stress network

Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) pathway play pivotal roles in cancer progression and therapy resistance, yet their pan-cancer dynamics and clinical implications remain poorly understood. This study presents a comprehensive analysis of ER stress and UPR pathway activity across 32 cancer types using The Cancer Genome Atlas (TCGA) data. By integrating gene-centric and pathway-centric approaches, including single-sample Gene Set Enrichment Analysis (ssGSEA), we characterized the expression landscape, tumor microenvironment interactions, and clinical relevance of UPR signaling. Our results revealed coordinated ER stress gene expression patterns in primary tumors, with UPR pathway activity significantly elevated in most cancers compared to adjacent normal tissues. Tumor purity inversely correlated with ER stress activity, underscoring microenvironmental influences. Differential expression analysis identified 61 UPR-related genes dysregulated across cancers, with IRE1 and PERK branches predominantly upregulated. Clinically, elevated UPR activity correlated with poor prognosis, advanced tumor stages, and resistance to therapies targeting EGFR, chromatin remodeling, and DNA repair. Co-expression networks highlighted UPR interactions with DNA repair and extracellular matrix pathways, while hallmark pathway analysis linked UPR to mTORC1 signaling, hypoxia, and epithelial-mesenchymal transition. Immune profiling revealed UPR-associated shifts in cytotoxic T cells and macrophages, suggesting microenvironmental modulation. Drug response analysis demonstrated UPR-mediated resistance to EGFR inhibitors and PARP inhibitors, implicating IRE1 as a key contributor. This study establishes the UPR as a central regulator of cancer progression, offering insights into its dual roles in tumor survival and therapy resistance. Our findings advocate for UPR pathway inhibition as a promising strategy to enhance treatment efficacy, particularly in lung, gastrointestinal, and kidney cancers.