Advancements in precision oncology over the past decades have led to new therapeutic interventions, but the efficacy of such treatments is generally limited by an adaptive process that fosters drug resistance¹. In addition to genetic mutations², recent research has identified a role for non-genetic plasticity in transient drug tolerance³ and the acquisition of stable resistance^4,5. However, the dynamics of cell-state transitions that occur in the adaptation to cancer therapies remain unknown and require a systems-level longitudinal framework. Here we demonstrate that resistance develops through trajectories of cell-state transitions accompanied by a progressive increase in cell fitness, which we denote as the ‘resistance continuum’. This cellular adaptation involves a stepwise assembly of gene expression programmes and epigenetically reinforced cell states underpinned by phenotypic plasticity, adaptation to stress and metabolic reprogramming. Our results support the notion that epithelial-to-mesenchymal transition or stemness programmes—often considered a proxy for phenotypic plasticity—enable adaptation, rather than a full resistance mechanism. Through systematic genetic perturbations, we identify the acquisition of metabolic dependencies, exposing vulnerabilities that can potentially be exploited therapeutically. The concept of the resistance continuum highlights the dynamic nature of cellular adaptation and calls for complementary therapies directed at the mechanisms underlying adaptive cell-state transitions.

过去几十年来，精准肿瘤学的进步导致了新的治疗干预措施，但这种治疗的疗效通常受到促进耐药性的适应性过程的限制¹。除了基因突变² 之外，最近的研究还确定了非遗传可塑性在瞬时药物耐受性³ 和获得稳定耐药^{性 4,5} 中的作用。然而，在适应癌症治疗过程中发生的细胞状态转换的动力学仍然未知，需要一个系统级的纵向框架。在这里，我们证明了抗性是通过细胞状态转换的轨迹发展的，伴随着细胞适应性的逐渐增加，我们将其表示为“抗性连续体”。这种细胞适应涉及基因表达程序和表观遗传增强细胞状态的逐步组装，其基础是表型可塑性、对压力的适应和代谢重编程。我们的结果支持这样一种观点，即上皮-间充质转化或干性程序（通常被认为是表型可塑性的代表）能够适应，而不是完全抵抗机制。通过系统的遗传扰动，我们确定了代谢依赖性的获得，暴露了可能在治疗中利用的脆弱性。耐药连续体的概念强调了细胞适应的动态性质，并呼吁针对适应性细胞状态转换的潜在机制进行补充疗法。