Background

The ability of cancer cells to develop treatment resistance is one of the primary factors that prevent successful treatment. Although initially thought to be dysfunctional in cancer, mitochondria are significant players that mediate treatment resistance. Literature indicates that cancer cells reutilize their mitochondria to facilitate cancer progression and treatment resistance. However, the mechanisms by which the mitochondria promote treatment resistance have not yet been fully elucidated.

Conclusions and perspectives

Here, we describe various means by which mitochondria can promote treatment resistance. For example, mutations in tricarboxylic acid (TCA) cycle enzymes, i.e., fumarate hydratase and isocitrate dehydrogenase, result in the accumulation of the oncometabolites fumarate and 2-hydroxyglutarate, respectively. These oncometabolites may promote treatment resistance by upregulating the nuclear factor erythroid 2–related factor 2 (Nrf2) pathway, inhibiting the anti-tumor immune response, or promoting angiogenesis. Furthermore, stromal cells can donate intact mitochondria to cancer cells after therapy to restore mitochondrial functionality and facilitate treatment resistance. Targeting mitochondria is, therefore, a feasible strategy that may dampen treatment resistance. Analysis of tumoral DNA may also be used to guide treatment choices. It will indicate whether enzymatic mutations are present in the TCA cycle and, if so, whether the mutations or their downstream signaling pathways can be targeted. This may improve treatment outcomes by inhibiting treatment resistance or promoting the effectiveness of anti-angiogenic agents or immunotherapy.

中文翻译：

---

线粒体对癌症治疗耐药性的影响

背景

癌细胞产生治疗抗性的能力是阻碍成功治疗的主要因素之一。尽管最初被认为在癌症中功能失调，但线粒体是介导治疗抵抗的重要参与者。文献表明，癌细胞重新利用其线粒体来促进癌症进展和治疗抵抗。然而，线粒体促进治疗抗性的机制尚未完全阐明。

结论和观点

在这里，我们描述了线粒体可以促进治疗抵抗的各种方式。例如，三羧酸(TCA)循环酶，即富马酸水合酶和异柠檬酸脱氢酶的突变，分别导致癌代谢物富马酸和2-羟基戊二酸的积累。这些癌代谢物可能通过上调核因子红细胞 2 相关因子 2 (Nrf2) 通路、抑制抗肿瘤免疫反应或促进血管生成来促进治疗耐药性。此外，基质细胞可以在治疗后将完整的线粒体捐赠给癌细胞，以恢复线粒体功能并促进治疗抵抗。因此，靶向线粒体是一种可行的策略，可以抑制治疗耐药性。肿瘤 DNA 分析也可用于指导治疗选择。它将表明 TCA 循环中是否存在酶突变，如果存在，是否可以靶向突变或其下游信号通路。这可以通过抑制治疗抵抗或促进抗血管生成剂或免疫疗法的有效性来改善治疗结果。