CD74 in hematological malignancies: from MHC chaperone to therapeutic target

CD74, originally known as the invariant chain of Major Histocompatibility Complex Class II Molecules (MHC class II), has now been acknowledged as a versatile signaling nexus and a universal lymphoma antigen. It has a pivotal role in the maturation, stimulation, and viability of various immune cells, such as B cells, T cells, Regulatory T Cells (Tregs), monocytes, and macrophages. It is extensively and significantly expressed in a variety of hematologic cancers, encompassing acute and chronic leukemias, lymphomas, and multiple myeloma. Given its expression pattern, along with its swift internalization and limited expression in most normal tissues, CD74 emerges as a promising target for a wide array of therapeutic approaches like antibody-drug conjugates (ADCs), bispecific antibodies, and Chimeric Antigen Receptor T-cell (CAR-T) therapy. However, the downstream signaling network of CD74 is highly context-dependent, playing a dual role in physiological immune regulation and pathological pro-cancer survival.