Upregulation of mitochondrial respiration coupled with high ROS-scavenging capacity is a characteristic shared by drug-tolerant cells in several cancers. As translational fidelity is essential for cell fitness, protection of the mitochondrial and cytosolic ribosomes from oxidative damage is pivotal. While mechanisms for recognising and repairing such damage exist in the cytoplasm, the corresponding process in the mitochondria remains unclear.By performing Ascorbate PEroXidase (APEX)-proximity ligation assay directed to the mitochondrial matrix followed by isolation and sequencing of RNA associated to mitochondrial proteins, we identified the nuclear-encoded lncRNA ROSALIND as an interacting partner of ribosomes. ROSALIND is upregulated in recurrent tumours and its expression can discriminate between responders and non-responders to immune checkpoint blockade in a melanoma cohort of patients. Featuring an unusually high G content, ROSALIND serves as a substrate for oxidation. Consequently, inhibiting ROSALIND leads to an increase in ROS and protein oxidation, resulting in severe mitochondrial respiration defects. This, in turn, impairs melanoma cell viability and increases immunogenicity both in vitro and ex vivo in preclinical humanised cancer models. These findings underscore the role of ROSALIND as a novel ROS buffering system, safeguarding mitochondrial translation from oxidative stress, and shed light on potential therapeutic strategies for overcoming cancer therapy resistance.

线粒体呼吸的上调加上高活性氧清除能力是多种癌症中耐药细胞的共同特征。由于翻译保真度对于细胞健康至关重要，因此保护线粒体和胞质核糖体免受氧化损伤至关重要。虽然细胞质中存在识别和修复此类损伤的机制，但线粒体中的相应过程仍不清楚。通过针对线粒体基质进行抗坏血酸过氧化酶 (APEX) 邻近连接测定，然后对与线粒体蛋白相关的 RNA 进行分离和测序，我们确定核编码的 lncRNA ROSALIND是核糖体的相互作用伙伴。 ROSALIND在复发性肿瘤中表达上调，其表达可以区分黑色素瘤患者队列中对免疫检查点阻断的反应者和无反应者。 ROSALIND具有异常高的 G 含量，可用作氧化底物。因此，抑制ROSALIND会导致 ROS 和蛋白质氧化增加，导致严重的线粒体呼吸缺陷。这反过来又损害了黑色素瘤细胞的活力，并增加了临床前人源化癌症模型中体外和离体的免疫原性。这些发现强调了ROSALIND作为一种新型 ROS 缓冲系统的作用，保护线粒体翻译免受氧化应激，并揭示了克服癌症治疗耐药性的潜在治疗策略。