Fucosyltransferase 8‐Derived Circular RNA Drives M2 Polarization of Macrophages Through ENO1 ‐ TNF Signaling Axis to Promote Lung Cancer Progression

Background Lung cancer, representing a predominant form of pulmonary malignancy, demonstrates significant disease burden and poor clinical outcomes. Circular RNAs (circRNAs) have emerged as critical regulators in various cancers, including lung cancer. However, the specific roles and mechanisms of circRNAs in lung cancer remain largely unexplored. Methods Differential circRNA expression was analyzed using GEO datasets GSE101586 and GSE112214. CircFUT8 was prioritized for its upregulation in lung cancer tissues. In vitro and in vivo functional experiments evaluated its effects on cell proliferation, apoptosis, migration, and invasion. RNA pull‐down, immunofluorescence, and western blotting assessed interactions with ENO1. Macrophage polarization was examined via cocultures and flow cytometry. Results CircFUT8 (hsa_circ_0003028) was significantly upregulated in lung cancer tissues, correlating with advanced stages and poor prognosis. It enhanced lung cancer cell proliferation, migration, and invasion while inhibiting apoptosis in cellular and animal models. Mechanistically, circFUT8 directly binds ENO1 to form an RNA‐protein complex, promoting M2 macrophage polarization. Silencing circFUT8 reversed these effects by suppressing ENO1 and M2 polarization, inhibiting tumor progression. Moreover, ENO1 promotes TNF signaling through glycolytic metabolites. Conclusions Our findings highlight the critical role of circFUT8 in lung cancer progression through its regulation of M2 macrophage polarization via interaction with ENO1. The findings suggest that circFUT8 may serve as both a diagnostic marker and a promising therapeutic target in lung cancer management. This study first identified the regulating oncogenic role of circFUT8 in lung cancer progression and the microenvironment.