Cancer stem cells (CSCs) are a distinct population of cells within tumors with capabilities of self-renewal and tumorigenicity. CSCs play a privotal role in cancer progression, metastasis, and relapse and tumor resistance to cytotoxic therapy. Emerging scientific evidence indicates that CSCs adopt several mechanisms, driven by cellular plasticity, senescence and quiescence, to maintain their self-renewal capability and to resist tumor microenvironmental stress and treatments. This poses major hindrances for CSC-targeting anti-cancer therapies: cell plasticity maintains stemness in CSCs and renders tumor cells to acquire stem-like phenotypes, contributing to tumor heterogeneity and CSC generation; cellular senescence induces genetic reprogramming and stemness activation, leading to CSC-mediated tumor progression and metastasis; cell quienscence facilitates CSC to overcome their intrinsic vulnerabilities and therapeutic stress, inducing tumor relapse and therapy resistance. These mechanisms are subjected to spatiotemporal regulation by hypoxia, CSC niche, and extracellular matrix in the tumor microenvironment. Here we integrate the recent advances and current knowledge to elucidate the mechanisms involved in the regulation of plasticity, senescence and quiescence of CSCs and the potential therapeutic implications for the future.

癌症干细胞 (CSC) 是肿瘤内具有自我更新和致瘤能力的独特细胞群。CSC 在癌症进展、转移和复发以及肿瘤对细胞毒性治疗的耐药性方面发挥着重要作用。新出现的科学证据表明，CSC 采用多种机制，由细胞可塑性、衰老和静止驱动，以保持其自我更新能力并抵抗肿瘤微环境压力和治疗。这对靶向 CSC 的抗癌疗法构成了主要障碍：细胞可塑性维持 CSC 的干性并使肿瘤细胞获得干细胞样表型，从而促进肿瘤异质性和 CSC 的产生；细胞衰老诱导基因重编程和干性激活，导致 CSC 介导的肿瘤进展和转移；细胞静止有助于 CSC 克服其固有的脆弱性和治疗压力，从而诱导肿瘤复发和治疗耐药性。这些机制受到肿瘤微环境中缺氧、CSC 生态位和细胞外基质的时空调节。在这里，我们整合了最新进展和当前知识，以阐明 CSC 的可塑性、衰老和静止调节所涉及的机制以及对未来的潜在治疗意义。