Tumor-Derived Exosomal circAP2B1 Induces M2 Macrophage Polarization by Enhancing Mitochondrial Homeostasis to Promote...

Esophageal squamous cell carcinoma (ESCC) remodels the immunosuppressive tumor microenvironment via exosome-mediated intercellular communication. In this study, circular RNA circAP2B1 is identified as a critical regulatory molecule that is markedly upregulated in ESCC tissues and patient serum and strongly associated with poor prognosis. Mechanistically, tumor-derived exosomes efficiently deliver circAP2B1 to tumor-associated macrophages (TAMs), where it serves as a distinct molecular scaffold that simultaneously binds the transcription factor ESRRA and the nuclear import receptor KPNA1, facilitating ternary complex formation and ESRRA nuclear translocation. Once in the nucleus, ESRRA directly activates the transcription of Mitofusin 2 (MFN2), a pivotal regulator of mitochondrial fusion, thereby enhancing mitochondrial oxidative phosphorylation, improving ATP production efficiency, and establishing a metabolically optimized intracellular environment that ultimately drives TAMs toward a pro-tumor M2 phenotype. Both in vitro and in vivo experiments demonstrate that targeted intervention of the circAP2B1/ESRRA/KPNA1/MFN2 signaling axis effectively reverses M2 polarization and markedly suppresses tumor progression. This study uncovers a novel exosomal circRNA-mediated metabolic-immune regulatory pathway and offers new avenues for the diagnosis and treatment of ESCC. The findings not only expand the understanding of circRNA functions in tumor immunity but also provide a theoretical basis for the development of therapies targeting the metabolic-immune axis.