MAN1B1 (mannosidase alpha class 1B member 1) is an endoplasmic reticulum (ER) glycoprotein quality control enzyme that trims alpha-1,2-linked mannose residues from N-linked oligosaccharides, converting Man(9)GlcNAc(2) to Man(8)GlcNAc(2) and further processing to Man(5-6)GlcNAc(2) at high concentrations 1. The enzyme functions within the ER quality control compartment as part of the ER-associated protein degradation (ERAD) pathway, targeting misfolded glycoproteins for lysosomal degradation 2. MAN1B1 operates within a selective degradation complex that recognizes densely glycosylated substrates, particularly viral envelope glycoproteins, directing them to lysosomes independently of polyubiquitination 2. In cancer pathology, MAN1B1 is aberrantly overexpressed and stabilized through ERK-HRD1 signaling in bladder cancer, where it mediates CD47 glycosylation to promote immune evasion and tumor progression 1. MAN1B1 upregulation in hepatocellular carcinoma occurs through HBX-enhanced GRP78 stability via TRIM25, activating PI3K/mTOR signaling 3. Loss-of-function mutations in MAN1B1 cause Rafiq syndrome (MAN1B1-CDG), an autosomal recessive congenital disorder of glycosylation characterized by intellectual disability, developmental delay, facial dysmorphism, hypotonia, and hypertransaminasemia 4. MAN1B1 represents a promising therapeutic target for cancer immunotherapy without the anemia risk associated with anti-CD47 antibodies 1.