Endoplasmic reticulum stress regulators exhibit different prognostic, therapeutic and immune landscapes in pancreatic adenocarcinoma

Endoplasmic reticulum stress (ERS) and unfolded protein response are the critical processes of tumour biology. However, the roles of ERS regulatory genes in pancreatic adenocarcinoma (PAAD) remain elusive. A novel ERS‐related risk signature was constructed using the Lasso regression analysis. Its prognostic value, immune effect, metabolic influence, mutational feature and therapeutic correlation were comprehensively analysed through multiple bioinformatic approaches. The biofunctions of KDELR3 and YWHAZ in pancreatic cancer (PC) cells were also investigated through colony formation, Transwell assays, flow cytometric detection and a xenograft model. The upstream miRNA regulatory mechanism of KDELR3 was predicted and validated. ERS risk score was identified as an independent prognostic factor and could improve traditional prognostic model. Meanwhile, it was closely associated with metabolic reprogramming and tumour immune. High ERS risk enhanced glycolysis process and nucleotide metabolism, but was unfavourable for anti‐tumour immune response. Moreover, ERS risk score could act as a potential biomarker for predicting the efficacy of ICBs. Overexpression of KDELR3 and YWHAZ stimulated the proliferation, migration and invasion of SW1990 and BxPC‐3 cells. Silencing KDELR3 suppressed tumour growth in a xenograft model. miR‐137 could weaken the malignant potentials of PC cells through inhibiting KDELR3 (5′‐AGCAAUAA‐3′). ERS risk score greatly contributed to PAAD clinical assessment. KDELR3 and YWHAZ possessed cancer‐promoting capacities, showing promise as a novel treatment target.