LRP1B (LDL receptor related protein 1B) is a large cell surface receptor protein that functions in receptor-mediated endocytosis, binding and internalizing ligands at the plasma membrane 1. As a member of the LDLR protein family, LRP1B performs cargo transport and cell signaling functions 1. The protein is frequently altered in human cancers, with LRP1B being among the most commonly mutated genes across cancer types 12. LRP1B alterations are consistently found in gastric cancer alongside TP53 and ARID1A mutations 2, and mutations occur in lung cancers including SMARCA4-deficient NSCLC 3 and brain metastases 4. In cervical cancer, HPV integration into LRP1B introns downregulates protein expression 5. Beyond oncology, LRP1B variants are associated with accelerated progression to dementia in Parkinson's disease patients 6. The gene serves as a potential biomarker, with LRP1B mutations correlating with high tumor mutation burden and treatment response in rectal cancer 7. Despite being frequently inactivated and regarded as a putative tumor suppressor, LRP1B's exact mechanisms in cancer remain incompletely understood due to technical challenges associated with studying this giant protein 1.