Longevity & AgingMacrophage Mitochondrial Switch Boosts Anti-Tumor Immunity
Researchers at the University of Pennsylvania identified NDUFA4, a subunit of mitochondrial Complex IV, as a critical regulator of tumor-associated macrophage (TAM) function. In tumors, high NDUFA4 expression sustains pro-tumoral macrophages. Interferons reduce NDUFA4 via a conserved bifunctional RNA encoding both NDUFA4L3 and miR-147, shifting TAMs toward an anti-tumor IFN-activated state. This NDUFA4 repression triggers mitochondrial DNA release into the cytoplasm, activating the cGAS-STING pathway and amplifying interferon signaling. The result is increased NK and CD8+ T cell recruitment and stronger anti-tumor immunity. RNA-based therapeutics targeting the Ndufa4 transcript enhanced immune checkpoint blockade efficacy and suppressed B16 melanoma growth in mice, revealing a novel immunotherapeutic strategy.
