Clark Megan L, Simeonov Kamen P, Mowel Walter K, Michieletto Michaël F, Joannas Leonel, Wright Jasmine M, Erickson Isabel, Johnson Lexus R, Krishnan Rakesh, de la Fuente-Núñez César, Minn Andy J, Henao-Mejia Jorge
Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology and Immune Health (I3H), Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Translational Research Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Center for Metastasis Research eXcellence (MET-X), Fred Hutchinson Cancer Center, Seattle, WA 98109, USA; Penn Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Immunity. 2025 Jul 8;58(7):1670-1687.e12. doi: 10.1016/j.immuni.2025.06.006. Epub 2025 Jun 30.
Tumor-associated macrophages (TAMs) influence tumor progression and immune checkpoint blockade (ICB) efficacy. Interferon (IFN)-TAMs predict better survival and ICB responses, yet the mechanisms governing IFN-TAMs remain unclear. Here, we identify NDUFA4, a complex IV subunit of the electron transport chain, as a functional switch controlling TAM function and anti-tumor immunity. NDUFA4 expression sustained pro-tumoral TAMs. However, intratumoral IFNs decreased NDUFA4 expression in TAMs via the cooperative action of NDUFA4L3 and miR-147, co-encoded by a conserved bifunctional transcript. Mechanistically, NDUFA4 repression increased mitochondrial DNA release into the cytoplasm and subsequent STING activation, thereby amplifying anti-tumor IFN-induced transcriptional programs in TAMs. Finally, we designed RNA-based therapeutics that leveraged the specificity of miR-147 for the Ndufa4 transcript to enhance ICB efficacy and inhibit B16 melanoma tumor growth. These findings uncover mitochondrial complex IV remodeling as a critical mechanism governing the functional adaptation of macrophages to distinct microenvironments with broad implications for immunotherapy.
肿瘤相关巨噬细胞（TAM）影响肿瘤进展和免疫检查点阻断（ICB）疗效。干扰素（IFN）-TAM预示着更好的生存率和ICB反应，但调控IFN-TAM的机制仍不清楚。在此，我们确定电子传递链复合物IV亚基NDUFA4是控制TAM功能和抗肿瘤免疫的功能开关。NDUFA4的表达维持促肿瘤TAM。然而，肿瘤内的IFN通过由保守的双功能转录本共编码的NDUFA4L3和miR-147的协同作用降低了TAM中NDUFA4的表达。从机制上讲，NDUFA4的抑制增加了线粒体DNA释放到细胞质中并随后激活了STING，从而放大了TAM中抗肿瘤IFN诱导的转录程序。最后，我们设计了基于RNA的疗法，利用miR-147对Ndufa4转录本的特异性来增强ICB疗效并抑制B16黑色素瘤肿瘤生长。这些发现揭示了线粒体复合物IV重塑是控制巨噬细胞功能适应不同微环境的关键机制，对免疫治疗具有广泛影响。
