Researchers at The University of Texas MD Anderson Cancer Center have discovered that targeting a specific immune process could help improve recovery after nerve injury and reduce chronic pain.

Efferocytosis in health and disease. Efferocytosis integrates apoptotic cell recognition, engulfment, digestion, and reprogramming to link cell clearance with tissue repair. Molecular checkpoints bal...

Xi et al. identify an FN1+ macrophage subtype in esophageal cancer with high efferocytosis activity. They delineate a TP63-RAC2 transcriptional axis that drives this process, promoting M2 macrophage polarization and immunosuppression. Targeting this pathway impairs efferocytosis and suppresses tumor growth, revealing a therapeutic vulnerability.

Chemotherapy-induced efferocytosis drives ovarian cancer stem cell enrichment. By engulfing apoptotic cancer cells, macrophages upregulate ODC1 and produce putrescine, which elevates osteopontin (OPN) expression. Secreted OPN then activates the CD44 receptor on cancer cells, promoting stemness and chemoresistance. This study uncovers a macrophage–polyamine–OPN axis as a crucial pathway in post-chemotherapy relapse. Abstract Chemotherapy-induced enrichment of cancer stem cells (CSCs) is a key mechanism underlying acquired chemoresistance and recurrence of epithelial ovarian cancer (OC). Although chemotherapy may enrich CSCs through selection or by inducing dedifferentiation, the dynamic changes in the tumor niche and their impact on CSCs during chemotherapy remain unclear. In this study, single-cell sequencing and multiplex immunohistochemical analysis are used to define microenvironmental changes, and a post-chemotherapy increase in efferocytotic macrophages that phagocytosed chemotherapy-induced apoptotic tumor cells is identified. Efferocytotic macrophages are associated with poor prognosis and CSCs in OC. Their conditioned medium facilitates OC stemness in vitro. Meanwhile, targeting efferocytosis suppresses CSC enrichment, chemoresistance, and regrowth in vivo. Mechanistically, it is demonstrated that enhanced expression of ODC1 driven by efferocytosis increases polyamine flux, particularly putrescine, by integrating metabolomics and transcriptomics. The increase in putrescine content leads to the SPP1 and OPN overexpression in macrophages, conferring cancer stemness to OC cells through the OPN-CD44 axis. Treatment with an ODC1 selector inhibitor mitigates CSC enrichment, sensitizes tumors to cisplatin, and restricts tumor regrowth. Together, the study shows that efferocytosis and associated polyamine metabolic reprogramming support the chemotherapy-induced enrichment of CSCs, providing new targets for addressing chemoresistance and recurrence of OC.

This study reports early Piezo1 activation in bone marrow monocyte-derived macrophages (MoMs) during myocardial infarction (MI), which governs the fate and function of recruited macrophages. The recruited MoMs with increased Piezo1 expression exhibit increased ferroptosis and defective efferocytosis, delayed clearance of dead cells and resolution of inflammation, leading to the aggravation of post-MI cardiac remodeling and heart failure. Abstract The regulation of macrophage function, particularly that of monocyte-derived macrophages (MoMs), by mechanical forces during myocardial infarction (MI) remains poorly understood. Consistently upregulated Piezo1 expression in cardiac macrophages and MoMs post-MI is found. Elevated Piezo1 expression in MoMs directly contributes to increased Piezo1 levels in cardiac macrophages. Myeloid cell-specific Piezo1-deficient mice (Piezo1 Lyz2 ) exhibit significant improvements in ventricular function/remodeling after MI, accompanied by decreased apoptotic cardiomyocytes and decreased inflammation, increased numbers of macrophages, and increased border zone efferocytosis. In vitro, Piezo1 activation by Yoda1 increased oxygen-glucose deprivation (OGD)-induced ferroptosis and impaired MoM efferocytosis. Conversely, Piezo1 deficiency in MoMs decreases ferroptosis and increases efferocytosis. SLC7A11 is shown to mediate Piezo1-induced defective efferocytosis in MoMs. Piezo1 activation aggravated OGD-induced macrophage ferroptosis via Ca 2+ influx followed by SLC15A3 upregulation. Piezo1 upregulated SLC7A11 in macrophages via a Ca 2+ /ATF4-dependent pathway. MoM-specific SLC7A11 knockdown significantly increases efferocytosis, reduces cardiomyocyte apoptosis and inflammation, and ameliorates post-MI left ventricular remodeling and function. In conclusion, early Piezo1 activation in MoMs is identified during MI, which governs the fate and function of recruited macrophages. These data establish an ischemic heart–bone marrow functional network and provide a novel therapeutic strategy in which MoM Piezo1 is targeted for post–MI heart repair.

We reanalyzed several previously published datasets to train and validate our predictive model. The analysis included four bulk RNA sequencing cohorts (TCGA, METABRIC, GSE21653, and GSE58812) and four scRNA-seq datasets (GSE176078, GSE143423, GSE161529 and GSE114725). In total, 739 samples were...