宾夕法尼亚大学Jorge Henao-Mejia研究团队报道了肿瘤相关巨噬细胞线粒体复合体IV重塑放大干扰素信号并促进抗肿瘤免疫。相关论文发表在2025年6月30日出版的《免疫学》杂志上。

课题组发现NDUFA4是电子传递链的复合物IV亚基，是控制TAM功能和抗肿瘤免疫的功能开关。NDUFA4表达维持肿瘤前TAMs。

然而，肿瘤内IFN通过NDUFA4L3和miR-147的协同作用降低了TAMs中NDUFA4的表达，miR-147由保守的双功能转录物共同编码。从机制上讲，NDUFA4抑制增加了线粒体DNA释放到细胞质和随后的STING激活，从而放大了TAMs中抗肿瘤IFN诱导的转录程序。最后，该研究团队设计了基于RNA的治疗方法，利用miR-147对Ndufa4转录物的特异性来增强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体IV重塑是巨噬细胞对不同微环境的功能适应的关键机制，对免疫治疗具有广泛的意义。

据介绍，肿瘤相关巨噬细胞（TAMs）影响肿瘤进展和免疫检查点阻断（ICB）的疗效。干扰素(IFN)-TAMs预测更好的生存和ICB反应，但控制IFN-TAMs的机制尚不清楚。

附：英文原文

Title: Mitochondrial complex IV remodeling in tumor-associated macrophages amplifies interferon signaling and promotes anti-tumor immunity

Author: Megan L. Clark, Kamen P. Simeonov, Walter K. Mowel, Michal F. Michieletto, Leonel Joannas, Jasmine M. Wright, Isabel Erickson, Lexus R. Johnson, Rakesh Krishnan, César de la Fuente-Núez, Andy J. Minn, Jorge Henao-Mejia

Issue&Volume: 2025-06-30

Abstract: 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.

DOI: 10.1016/j.immuni.2025.06.006

Source: https://www.cell.com/immunity/abstract/S1074-7613(25)00275-4