The quantitative case is striking. In studies of anti-CD20 antibodies used against B-cell lymphomas, macrophages destroyed roughly 0.5 to 3 target cells each, whereas NK cells killed only about 0.04 to 0.1 targets per cell, a more than tenfold difference with no significant correlation between the two effects. Mouse experiments sealed the argument: when researchers depleted macrophages, the antitumor activity of rituximab against non-Hodgkin lymphoma vanished entirely, and selective removal of peritoneal macrophages almost completely eliminated the efficacy of the anti-EGFR antibody cetuximab in colorectal cancer models. Similar evidence establishes ADCP as the primary mechanism for trastuzumab in HER2-positive tumors and a key pathway in multiple myeloma, neuroblastoma, and mature T-cell and NK-cell malignancies.

At the molecular level, ADCP unfolds as a tightly choreographed three-step cascade. First, the antibody Fc domain binds Fc gamma receptors on the macrophage surface, where the balance between activating receptors such as FcγRI, FcγRIIa, and FcγRIIIa and the sole inhibitory receptor FcγRIIb determines whether the cell commits to engulfment. Second, receptor clustering in cholesterol-rich lipid rafts triggers Src family kinases to phosphorylate ITAM motifs, recruiting the Syk kinase and unleashing downstream signaling through PI3K, calcium flux, and Rho-family GTPases. Third, actin polymerization drives pseudopod extension around the opsonized target, forming a phagosome that matures through phosphoinositide remodeling, Rab and ARF GTPase switches, acidification, and fusion with lysosomes. Disrupt any link in this chain and antibody therapy loses much of its punch.

The review’s authors frame ADCP as an outcome-dependent, programmable process rather than a simple on-off switch, and they distinguish productive phagocytosis from its less useful cousins. Trogocytosis, in which effector cells strip membrane fragments without fully engulfing the target, can leave tumor cells viable while removing surface antigen, a route to immune escape seen with rituximab, trastuzumab, and cetuximab. Efferocytosis, the clearance of already-dead cells through phosphatidylserine receptors, tends to trigger anti-inflammatory, tissue-repair programs dominated by IL-10 and TGF-beta, potentially dampening antitumor immunity. Productive ADCP, by contrast, can feed degraded tumor antigens into MHC class II presentation and even MHC class I cross-presentation, bridging innate clearance to adaptive T-cell priming.

Yet the same process carries a paradox. After an initial burst of engulfment, macrophages can enter a state the authors call hypophagia, a phagocytic exhaustion driven by internalization and degradation of activating Fcγ receptors, particularly FcγRI, while inhibitory FcγRIIb is recycled back to the surface. Under high tumor burden, this intrinsic ceiling may rapidly curtail clearance and contribute to the limited durability of anti-CD20 and anti-CD38 antibodies. Worse, ADCP-experienced macrophages can be reprogrammed toward tumor-promoting states, upregulating PD-L1, IDO, and immunosuppressive chemokines that suppress T-cell and NK-cell activity. In one study, cetuximab binding to EGFR-positive tumor cells actually activated M2-like macrophages to release IL-10 and VEGF, illustrating how antibody therapy can inadvertently feed the very microenvironment it aims to destroy.

The tumor microenvironment itself stacks the deck against phagocytosis. Dense extracellular matrix slows antibody diffusion and, through integrin-dependent mechanotransduction, disrupts the cytoskeletal dynamics macrophages need to extend pseudopods. Hypoxia stabilizes HIF-1alpha, which transcriptionally upregulates inhibitory FcγRIIb on tumor-associated macrophages and CD47 on tumor cells. Lactate-driven acidosis weakens IgG binding to activating receptors and impairs Syk signaling, while TGF-beta and IL-10 reshape the FcγR repertoire toward suppression. Myeloid-derived suppressor cells add insult by secreting IL-10 and TGF-beta, producing arginase and reactive oxygen species, and even internalizing antibody-antigen complexes without killing the target, diverting opsonized cells away from functional macrophages.

Toxicity presents a further constraint that has repeatedly stalled clinical development. Because phagocytosis is triggered by antibody opsonization rather than true malignant specificity, strategies that lower the phagocytic threshold can also promote elimination of healthy cells, particularly in the hematopoietic compartment. The CD47-SIRPα axis illustrates the problem vividly: CD47 serves as a physiological marker of self on red blood cells and other normal tissues, so blocking it risks on-target, off-tumor destruction manifesting as anemia and thrombocytopenia. Several CD47-targeting agents, including CC-90002 and the SIRPα-fusion protein TTI-621, have seen their trials terminated after showing limited efficacy or safety concerns, underscoring that indiscriminate removal of phagocytic restraints compromises the therapeutic index.

The field is therefore shifting from phagocytosis maximization to phagocytosis optimization, and the review catalogs six major strategies. Fc engineering leads the way: the S239D/I332E double mutation can boost FcγRIIa affinity up to 70-fold, while removal of core fucose raises FcγRIIIa binding 20- to 50-fold, approaches already validated in approved drugs such as obinutuzumab and tafasitamab. Bispecific designs add precision, with a GPC3/CD47 bispecific antibody blocking don’t-eat-me signaling only on GPC3-positive liver cancer cells, and a CD47/CD24 bispecific sparing red blood cells while selectively clearing double-positive tumor cells. Blocking inhibitory FcγRIIb with antibodies such as NVS32b has restored rituximab and daratumumab efficacy in preclinical models, and reprogramming M2-like tumor-associated macrophages toward a pro-phagocytic M1 state, using TLR7/8 agonists like resiquimod or FcγRI-targeted CAR macrophages that cleared more than 80 percent of colorectal cancer cells in vitro, offers a cell-intrinsic route to stronger ADCP.

Clinical results already vindicate the approach in blood cancers. The GALLIUM trial showed obinutuzumab reduced progression or death risk by 34 percent versus rituximab-based therapy in follicular lymphoma, while daratumumab monotherapy cut progression risk by 51 percent in high-risk smoldering myeloma, earning 2025 FDA approval as the first therapy for that indication. Belantamab mafodotin, an afucosylated antibody-drug conjugate, achieved a median progression-free survival of 36.6 months in the DREAMM-7 trial, and tafasitamab’s Fc-engineered design delivered 22.4 months of median PFS in follicular lymphoma. In solid tumors, the biparatopic bispecific antibody zanidatamab achieved a 52 percent response rate in HER2-high biliary tract cancer, though agents like AFM24 and murlentamab highlight how microenvironmental barriers and modest single-agent activity can still derail development.

The authors close with a call for higher-resolution thinking. The blunt M1/M2 macrophage paradigm cannot capture how ontogeny, tissue location, metabolic state, and prior phagocytic experience shape therapeutic response, and their own pan-cancer analysis of 33 TCGA tumor types shows why context matters: macrophages made up 53.9 percent of immune cells in glioblastoma but only 11.1 percent in thymoma, M2-like cells dominated every cancer type except diffuse large B-cell lymphoma, and increased macrophage infiltration predicted worse outcomes in 15 cancer types but better outcomes in 9. Future progress, they argue, will depend on tumor-restricted antibody design, logic-gated bispecific platforms, biomarker-guided patient selection, and rational combinations that couple macrophage phagocytosis with T-cell and NK-cell immunity, so that the ultimate measure of success is not how much tumor gets eaten, but whether that engulfment translates into durable, patient-centered benefit.

Subject of Research: Mechanisms and therapeutic optimization of macrophage-mediated antibody-dependent cellular phagocytosis in cancer immunotherapy

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

Article References: Ju, M., Zhang, M., Ma, S., An, Y., Xiao, S., Xu, J., Li, N., Chen, Y., Wei, M., Wang, H., & Zhao, L. (2026). Optimizing antibody-dependent cellular phagocytosis for cancer immunotherapy: mechanisms, constraints, and therapeutic strategies. Journal of Advanced Research. https://doi.org/10.1016/j.jare.2026.10.003

Image Credits: AI Generated

DOI: 10.1016/j.jare.2026.10.003

Keywords: antibody-dependent cellular phagocytosis, macrophages, monoclonal antibodies, Fc gamma receptors, CD47-SIRPalpha axis, tumor-associated macrophages, Fc engineering, cancer immunotherapy, phagocytosis checkpoints, tumor microenvironment, rituximab, hypophagia