WNT5B is a Wnt family ligand that binds frizzled receptors to regulate both canonical and non-canonical Wnt signaling pathways. The protein is secreted and acts as a developmental signaling molecule with likely short-range paracrine effects. WNT5B activates frizzled-dependent cascades including the planar cell polarity (PCP) pathway via FZD3-DVL3-RAC1-JNK signaling 1 and regulates alternative Wnt signaling through Yes-associated protein (YAP) activation 2. In normal physiology, WNT5B promotes hematopoietic stem cell maturation and myeloid development via β-catenin-independent signaling 3 and supports hair follicle cycling through β-catenin pathway activation 4. WNT5B is frequently upregulated in multiple cancer types. In colorectal cancer, oncogenic KRAS activates the transcription factor TFCP2, which upregulates WNT5B to drive transformation of carcinoma-associated fibroblasts and tumor angiogenesis 5. In osteosarcoma, WNT5B expression correlates with metastasis and reduced survival; the ligand promotes cancer stem cell expansion, chemoresistance to methotrexate, and lung/liver metastasis through ROR1-dependent signaling 6. WNT5B similarly drives malignant phenotypes in non-small cell lung cancer and is expressed across esophageal and pancreatic cancer cell lines 7. Inhibition of WNT5B via ROR1-targeted antibodies reduces osteosarcoma stemness and represents a potential therapeutic approach 6.