Lung adenocarcinoma (LUAD) progression is strongly shaped by tumor-associated macrophages (TAMs), yet the post-transcriptional mechanisms that sustain matrix-remodeling TAM states remain incompletely understood. Here, circRNA profiling of LUAD TAMs versus normal tissue-resident macrophages identified circSMAD4 (hsacirc₀047713) as a consistently TAM-enriched circRNA associated with advanced clinicopathological features and unfavorable survival. circSMAD4 exhibited canonical circular properties, including a validated back-splice junction, RNase R resistance, and enhanced transcript stability. Functionally, circSMAD4 knockdown in human and murine macrophages attenuated tumor education, shifted macrophages away from an M2-like phenotype, and weakened their ability to promote LUAD-cell proliferation, invasion, and EMT-like changes in co-culture. In syngeneic orthotopic lung and experimental metastasis models, circSMAD4-depleted macrophages restrained tumor growth and reduced metastatic burden. Mechanistically, cytoplasmic circSMAD4 acted as a ceRNA to sequester miR-562 and relieve repression of COL4A1. In parallel, circSMAD4 formed a specific ribonucleoprotein complex with the m6A reader IGF2BP2, facilitating IGF2BP2 association with COL4A1, ACTA2, and SPI1 transcripts and enhancing their m6A-dependent stability. Together, these dual branches converge on a matrix-remodeling output, positioning circSMAD4 as a post-transcriptional hub that reinforces protumor TAM programs in LUAD and a potential target for microenvironment-directed therapy.
Yu et al. (Thu,) studied this question.