Aging-Associated Decline in Macrophage STAT6-OXPHOS Programs Promotes Tumor-Like Multinucleated Syncytia

Aging can alter macrophage functions through changes in intracellular processing, mitochondrial activity, and chronic inflammatory activation; however, whether aging-associated macrophage deregulation contributes to tumor-associated multinucleated syncytial formation remains poorly understood. Here, we investigated the role of aging macrophages in promoting tumor-like multinucleated syncytia and explored the underlying metabolic mechanisms. Immunohistochemical analyses of metastatic tissue sections from patients with prostate, breast, and lung cancers demonstrated enrichment of CD68+/panCK+ multinucleated tumor-like osteoclast syncytia in elderly patients. Using ex vivo co-culture systems, aged bone marrow-derived macrophages exhibited significantly increased propensity to generate multinucleated syncytia containing proliferative Ki67-positive cancer-associated nuclei. These syncytia displayed attenuated mitochondrial oxidative phosphorylation (OXPHOS) programs characterized by reduced oxygen consumption rates and decreased expression of mitochondrial respiratory proteins, such as ATP5a and SDHB. Pharmacologic inhibition of STAT6 further enhanced syncytial formation and suppressed OXPHOS-associated programs, whereas treatment with the EP2 antagonist C52 partially restored mitochondrial gene expression and reduced syncytial formation. Together, these findings identify a previously unrecognized aging-associated mechanism linking macrophage deregulation, attenuated STAT6-associated mitochondrial programs, and tumor-like multinucleated syncytial formation.