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Macrophages play vital roles in innate and adaptive immunity, and their functions are mediated via phagocytosis and antigen presentation. Despite the effort to identify phagocytic checkpoints and explore their mechanism of action, current checkpoint-scanning strategies cannot provide a complete and systematic list of such immune checkpoints. Here, we perform in vitro phagocytosis assays using primary healthy donor macrophages co-cultured with breast cancer cells followed by ribosome profiling of sorted macrophages, to identify immune system-specific checkpoints. We observe a downregulation of CD37 in phagocytic macrophages and demonstrate that targeting CD37 with a specific antibody promotes the phagocytosis of multiple cancer cells in vitro. Mechanistically, tumorous macrophage migration inhibitory factor (MIF) directly binds to CD37, promoting the phosphorylation of CD37Y13 and activating a transduction cascade that involves the recruitment of SHP1 and inhibition of AKT signaling, ultimately impairing phagocytosis. In vivo, targeting CD37 promotes tumor clearance in multiple preclinical mouse models and synergizes with anti-CD47 therapy. Thus, our study identifies a previously unidentified phagocytic checkpoint and provides new potential for precise therapy. Cancer cells evade the immune system by disrupting phagocytic clearance. Here, the authors identify CD37 as a potential checkpoint molecule expressed on non-phagocytes and propose that binding to tumor-derived MIF reduces the phagocytic ability via inhibiting the AKT pathway. In preclinical mouse models, anti-CD37-based therapy enhances phagocytosis by macrophages, facilitating tumor clearance.

Imaging macrophage trafficking in solid tumors has major implications for cancer diagnosis, prognosis, and therapy. Here, we show that macrophage labeling with lipid-shelled microbubbles enables ultrasound imaging at single-cell level. Crucially, microbubble labeling and sonication at low mechanical indexes do not affect macrophage viability, migration, phenotype, and cytokine secretion profile, supporting the notion that ultrasound imaging can be used for nondestructive macrophage imaging. Despite the damping exerted on the microbubble oscillations by the cellular compartments, the microbubbles exhibit highly nonlinear behavior upon sonication, allowing for high specificity nonlinear US imaging under in vitro and in vivo conditions. Subsequently, we demonstrate that nonlinear ultrasound imaging can selectively monitor macrophage accumulation and extravasation in solid tumors in rodents for at least 8?h after intravenous administration. These findings establish ultrasound as a noninvasive platform for immune cell trafficking in solid tumors and highlight its potential to advance cancer diagnosis, monitoring, and therapy. Imaging macrophage trafficking in solid tumors has implications for cancer diagnosis and prognosis. by labeling macrophages with lipid-shelled microbubbles in combination with ultrasound, the authors here achieve nondestructive in vivo intravenously administrated macrophage imaging at single cell level with 100??m resolution till 8?h in solid tumors in rodents.

SummaryMonocytes are critical to innate immunity, participating in chemotaxis during tissue injury, infection, and inflammatory conditions. However, the migration dynamics of human monocytes under different guidance cues are not well characterized. Here, we developed a microfluidic device to profile the migration characteristics of human monocytes under chemotactic and barotactic guidance cues while also assessing the effects of age and cytokine stimulation. Human monocytes preferentially migrated toward the CCL2 gradient through confined microchannels, regardless of donor age and migration pathway. Stimulation with interferon (IFN)-¦Ã, but not granulocyte-macrophage colony-stimulating factor (GM-CSF), disrupted monocyte navigation through complex paths and decreased monocyte CCL2 chemotaxis, velocity, and CCR2 expression. Additionally, monocytes exhibited a bias toward low-hydraulic-resistance pathways in asymmetric environments, which remained consistent across donor ages, cytokine stimulation, and chemoattractants. This microfluidic system provides insights into the unique migratory behaviors of human monocytes and is a valuable tool for studying peripheral immune cell migration in health and disease. Graphical abstract Highlights?The MAP chip profiles migration of human monocytes under various chemotactic and barotactic cues?Monocytes preferentially migrate toward CCL2 gradients, regardless of migration pathway and donor age?IFN-¦Ã reduces human monocyte chemotaxis, velocity, and CCR2 expression?Human monocytes show biased migration toward low-hydraulic-resistance pathways MotivationCell migration is fundamental to the biological processes that drive health and disease. While in?vivo models provide invaluable insights into cell migration within complex biological environments, precise control over the microenvironment and single-cell tracking is essential to deepen our understanding of the fundamental characteristics of cell migration. We present a high-throughput microfluidic platform, termed the migration analysis of peripheral immune cells (MAP) chip, that features four distinct sets of microchannels designed to assess the effects of both chemotactic and barotactic stimuli on cell migration at a single-cell level. By profiling human monocyte migration using the MAP chip, we demonstrated the utility of this device in characterizing migration of human monocytes under diverse conditions. Hall et?al. introduce the MAP chip, a microfluidic platform for profiling human monocytes under chemotactic and barotactic guidance cues. It reveals biased migration toward low-hydraulic-resistance pathways, disrupted migration upon cytokine stimulation, and consistent chemotaxis and barotaxis across donor ages¡ªenhancing our understanding of human monocyte migration characteristics.