KDELR1 is a seven-transmembrane receptor localized to the Golgi apparatus and endoplasmic reticulum (ER) membranes that primarily functions in retrieving ER-resident proteins bearing the C-terminal KDEL retention sequence 1. Beyond canonical ER protein recycling, KDELR1 engages diverse signaling pathways through heterotrimeric G-proteins, including activation of protein kinase A, Src tyrosine kinase, and Rab proteins, which regulate intracellular transport, extracellular matrix degradation, and plasma membrane protrusions 1. KDELR1 facilitates cell surface trafficking of protein disulfide isomerases (PDIs), enabling their extracellular functions in modifying integrin and ADAM17 disulfide bonds 2. Disease relevance is substantial: KDELR1 is upregulated across multiple malignancies including chondrosarcoma, head and neck squamous cell carcinoma, and lung adenocarcinoma, where elevated expression correlates with poor prognosis, drug resistance, and aggressive behavior 345. In chondrosarcoma, KDELR1 drives chemotherapy resistance through the Integrin-Hippo-YAP1 axis 3, while in head and neck cancer it promotes progression via Wnt/CTNNB1 signaling and associates with immunosuppressive tumor microenvironments 4. KDELR1 knockout impairs cell adhesion and ER stress responses, indicating essential roles in cellular homeostasis 6. These findings identify KDELR1 as a promising therapeutic target in cancer.