Facts and hopes in harnessing macrophage-mediated antibody-dependent cellular phagocytosis for cancer immunotherapy

Abstract Monoclonal antibodies (mAbs) used in the clinic can engage the immune system through their Fc domains, eliciting effector mechanisms such as, antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP). While natural killer (NK) cells have historically been implicated as the principal mediators of ADCC, emerging evidence suggests that tumour-associated macrophages (TAMs), particularly monocyte-derived subsets, play a central role in ADCP. These macrophages are abundant within the tumour microenvironment, express high levels of activating Fc gamma receptors (FcγRs), and retain robust phagocytic capacity. However, the heterogeneity of TAMs and the limited understanding of FcγR expression patterns across tumour types have constrained the therapeutic exploitation of ADCP. This review critically examines the contribution of macrophage-mediated ADCP to the activity of both tumour-targeting and immune-regulatory mAbs. We discuss how FcγR polymorphisms, isotype engineering, and antibody effector functions influence therapeutic efficacy, with particular attention to commonly used tumour targeting and immunomodulatory antibodies. The role of inhibitory receptors such as FcγRIIb, CD47, and PD-1 in modulating ADCP is also addressed. Advances in multispecific antibodies targeting tumour antigens alongside ADCP regulators, and preclinical data highlighting the importance of FcγR engagement, underscore the untapped potential of this pathway. We highlight key challenges, including TAM heterogeneity and macrophage hypophagia. Emerging strategies integrating synthetic biology and FcγR profiling may enable the rational design of therapies that selectively enhance ADCP. Macrophage-mediated ADCP represents a promising but underexploited axis in cancer immunotherapy, warranting further mechanistic investigation and translational development.