MPEG1 (macrophage expressed 1), also known as Perforin-2, is an ancient pore-forming protein belonging to the MACPF/CDC superfamily that serves as a critical intracellular immune effector 1. In dendritic cells, MPEG1 mediates antigen cross-presentation by forming pores in antigen-containing compartments, promoting antigen release into the cytosol for MHC class I presentation and CD8+ T-cell priming 2. Within phagocytes, MPEG1 functions as a pivotal bactericidal molecule that destroys phagocytosed gram-positive and gram-negative bacteria; MPEG1-deficient mice demonstrate increased susceptibility to infectious doses that wild-type mice survive 3. MPEG1 expression is upregulated by proinflammatory signals including TNFα and LPS, and requires low pH environments such as phagosomes for pore formation 1. Clinically, germline MPEG1 mutations cause Immunodeficiency 77 and are associated with recurrent pulmonary mycobacterial infections in humans 3. MPEG1 mutations have also been identified in diffuse large B-cell lymphoma subtyping algorithms, where the MCD-like genetic subtype containing MPEG1 mutations associates with poor prognosis and NF-κB activation 4. Additionally, MPEG1 shows promise as a diagnostic biomarker in dendritic cell-mediated immune responses relevant to IgA nephropathy 2. Evolutionarily, MPEG1 represents one of the oldest MACPF proteins, predating perforin from which it likely originated ~500 million years ago 5.