定向治疗已成为癌症治疗的重要手段，但其长期疗效受到药物耐受性的影响。获得性治疗耐药性主要分为两个阶段——首先是非遗传性药物容忍性的适应性发展，其次是通过获得性基因突变稳定的抗药性。药物耐受性已被描述在几乎所有临床癌症治疗情境中，并且可检测的耐药性肿瘤与治疗复发和生存不良密切相关。因此，需要新的治疗策略来克服癌症治疗耐受性。最近的研究发现，线粒体机制在定义癌细胞对定向治疗的敏感性方面起着至关重要的作用，同时已知已经确立的癌症治疗对线粒体产生出人意料的影响。在这里，我们强调了最近的研究，强调了一个新兴的三联疗法的概念，其中包括三个目标不同癌细胞易感性的化合物，但至少包括一个针对线粒体的化合物。这些针对线粒体的三联疗法在克服癌症治疗耐受性方面具有非常有前途的临床前效果。还讨论了如何克服将线粒体作为靶点的三联疗法在临床转化中面临的挑战的潜在策略。版权所有，未经许可，不得转载。

Targeted therapies have become a mainstay in the treatment of cancer, but their long-term efficacy is compromised by acquired drug resistance. Acquired therapy resistance develops via two phases - first through adaptive development of non-genetic drug tolerance which is followed by stable resistance through acquisition of genetic mutations. Drug tolerance has been described in practically all clinical cancer treatment contexts, and detectable drug-tolerant tumors are highly associated with treatment relapse and poor survival. Thereby novel therapeutic strategies are needed to overcome cancer therapy tolerance. Recent studies have identified a critical role of mitochondrial mechanisms in defining cancer cell sensitivity to targeted therapies and the surprising effects of established cancer therapies on mitochondria. Here, these recent studies are reviewed emphasizing an emerging concept of triplet therapies including three compounds targeting different cancer cell vulnerabilities, but including at least one compound that targets the mitochondria. These mitochondria-targeting triplet therapies have very promising preclinical effects in overcoming cancer therapy tolerance. Potential strategies of how to overcome challenges in clinical translation of mitochondria targeting triplet therapies are also discussed.This article is protected by copyright. All rights reserved.