Why antibody isotype matters for immunotherapy

Abstract Monoclonal antibodies (mAbs), engineered to recognize disease-associated antigens, are central to cancer immunotherapy due to their ability to block or eliminate malignant cells by engaging immune effector mechanisms. Yet many tumors evade or suppress these responses, and many patients fail to achieve durable clinical benefit, highlighting the need to optimize antibody-based strategies. A critical determinant of mAb activity is antibody isotype, which governs interactions with Fc receptors, complement pathways, and immune effector cells. While most approved therapeutics employ human IgG1 for its robust immune-stimulating capacity, growing evidence suggests that deliberate, context-dependent isotype selection could improve therapeutic efficacy. Here, we review the structural and functional properties of human IgG and IgA subclasses, with a focus on anti-CD20 rituximab in two- and three-dimensional models of human B-cell lymphoma. We further discuss how antigen density, tumor architecture, and host variables influence antibody-mediated effector functions. Together, these considerations highlight opportunities to refine antibody isotype selection for more individualized cancer immunotherapy.