Optimizing antibody-dependent cellular phagocytosis for cancer immunotherapy: mechanisms, constraints, and therapeutic strategies

Background Accumulating evidence demonstrates that antibody-dependent cellular phagocytosis (ADCP), mediated by tumor-associated macrophages via Fcγ receptors (FcγR), represents a key Fc-dependent effector mechanism for selected antitumor monoclonal antibodies, including rituximab in B-cell malignancies, trastuzumab in HER2-positive cancers, cetuximab in EGFR-expressing tumors, and daratumumab in multiple myeloma. Beyond direct tumor cell clearance, macrophage-driven ADCP acts as a critical innate-adaptive immune bridge by facilitating antigen processing, intercellular immune crosstalk and downstream adaptive immune activation. However, ADCP is not uniformly beneficial. Depending on target antigen properties, macrophage functional state, and tumor microenvironmental cues, excessive or dysregulated ADCP may instead drive macrophage dysfunction, immunosuppressive remodeling, adaptive resistance, and dose-limiting toxicities. These observations highlight the need for a more selective and mechanistically informed framework for understanding and therapeutically harnessing ADCP in cancer immunotherapy.Aim of review This review summarizes the molecular regulation of ADCP, including FcγR signaling, cytoskeletal dynamics, phagosome formation and maturation, and phagocytosis checkpoint control, and discusses how these mechanisms shape phagocytic quality and therapeutic outcomes. We propose a conceptual shift from phagocytosis maximization to phagocytosis optimization and highlight strategies to improve the efficacy and safety of ADCP-based cancer immunotherapy.Key scientific concepts of review This review emphasizes four key concepts. First, it outlines the molecular cascade governing ADCP from FcγR-mediated signaling to phagosome maturation and degradation. Second, it highlights the dual roles of ADCP in tumor immunity, showing that productive ADCP promotes tumor clearance and immune priming, whereas dysregulated ADCP drives immunosuppression and toxicity. Third, it proposes that therapeutic ADCP should be defined by tumor selectivity and durable immune activation rather than engulfment alone. Fourth, it summarizes six major strategies to enhance beneficial ADCP, including Fc engineering, antigen-binding optimization, FcγRIIb blockade, targeting "don't-eat-me" signals, macrophage reprogramming, and combination with immune checkpoint inhibitors.