Macrophage phagocytosis checkpoints in DLBCL immunotherapy: an evidence-maturity framework from CD47 to CD200

Abstract

Diffuse large B-cell lymphoma (DLBCL) is treated with an expanding range of antibody- and cell-based therapies, yet macrophage phagocytosis checkpoints are still often discussed one molecule at a time. Here, we ask how far the evidence for each major axis has actually progressed in DLBCL immunotherapy. We considered five areas of support: lymphoma protein-level evidence, antibody-dependent cellular phagocytosis (ADCP), in vivo lymphoma data, clinical lymphoma evidence, and biomarker or predictive relevance. CD47/SIRPalpha remains the reference point because it has the broadest mechanistic, lymphoma, and clinical support. Major histocompatibility complex class I (MHC-I)/leukocyte immunoglobulin-like receptor B1 (LILRB1) and CD39/CD73-adenosine signaling have meaningful lymphoma-related functional evidence but remain less mature clinically. CD24/Siglec-10 is still best regarded as candidate/emerging. CD200/CD200R sits at a different stage: its myeloid biology, receptor structure, and Dok2-RasGAP signaling make it a credible candidate, but a direct DLBCL experiment showing restoration of anti-CD20 ADCP after pathway blockade is still lacking. We also consider how these pathways may be shaped by Fc receptor competence, spatial tumor-macrophage contact, anti-CD19 therapy, bispecific antibodies, and CAR-T-cell therapy. The purpose of the framework is practical: to separate what is already supported in lymphoma from what still needs to be tested before clinical claims are made.