In patients with cancer with metastatic disease, the rate of complete tumor response to systemic therapies is low, and residual lesions persist in the majority of patients due to early molecular adaptation in cancer cells. A growing body of evidence suggests that a subpopulation of drug-tolerant persister cells—a reversible phenotype characterized by reduced drug sensitivity and decreased cell proliferation—maintains residual disease and may serve as a reservoir for resistant phenotypes. The survival of these residual tumor cells can be caused by reactivation of specific signaling pathways, phenotypic plasticity (i.e., transdifferentiation), epigenetic or metabolic reprogramming, downregulation of apoptosis as well as transcriptional remodeling. In this review, we discuss the molecular mechanisms that enable adaptive survival in drug-tolerant cells. We describe the main characteristics and dynamic nature of this persistent state, and highlight the current therapeutic strategies that may be used to interfere with the establishment of drug-tolerant cells, as an alternative to improve objective response to systemic therapies and delay the emergence of resistance to improve long-term survival.

中文翻译：

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癌症全身治疗药物耐受的细胞内在机制

在患有转移性疾病的癌症患者中，肿瘤对全身治疗的完全反应率很低，并且由于癌细胞的早期分子适应，残留病灶在大多数患者中持续存在。越来越多的证据表明，耐受药物的持久细胞亚群——一种以药物敏感性降低和细胞增殖减少为特征的可逆表型——维持残留疾病，并可能作为耐药表型的储存库。这些残留肿瘤细胞的存活可能是由特定信号通路的重新激活、表型可塑性（即转分化）、表观遗传或代谢重编程、细胞凋亡的下调以及转录重塑引起的。在本次审查中，我们讨论了在耐药细胞中实现适应性生存的分子机制。我们描述了这种持续状态的主要特征和动态性质，并强调了当前可用于干扰耐药细胞建立的治疗策略，作为改善对全身治疗的客观反应和延缓耐药性出现的替代方法以提高长期生存率。