Multifunctional CD38 in the pathogenesis and treatment of B-cell lymphomas.

B-cell lymphoma is a group of non-Hodgkin lymphomas with high heterogeneity. Despite advancement in therapeutics, the clinical outcomes of B-cell lymphomas need to be improved. CD38, a transmembrane multifunctional protein, is widely expressed across various B-cell lymphoma subtypes. Research indicates that CD38 plays multiple pathogenic roles in B-cell lymphomas, including regulation of proliferation, apoptosis, immune modulation, primarily through its enzymatic activity and its influence on signaling pathways in malignant lymphoma cells and immunosuppressive cells, making it a valuable therapeutic target. In recent years, CD38-targeted therapies, such as anti-CD38 antibodies and CD38-directed CAR-T cell therapies, have been explored for B-cell lymphomas. This review summarizes the knowledge on CD38 molecular functions, data of CD38 heterogeneous expression and prognostic role in B-cell lymphomas (from indolent to aggressive subtypes), anti-CD38 antibody efficacy and mechanisms of action, current understanding of the treatment resistance mechanisms, frontier advances in CD38-targeted therapies, and the challenges of novel targeted and immunotherapies in clinical applications, thereby seeking to provide a deep understanding of the role of CD38 in the pathogenesis and treatment of B-cell lymphomas. CD38-targed therapy is especially promising as a novel and optional treatment for CD20-negative lymphomas, for which standard treatment has not been established. Although the efficacy of anti-CD38 antibodies in most other B-cell lymphomas is low in previous clinical trials, in contrast to the remarkable efficacy of daratumumab in multiple myeloma, novel therapeutic strategies and combination therapies in ongoing clinical trials have the potential to overcome the counteracting actions and to improve the clinical outcomes of patients with relapsed/refractory B-cell lymphoma.