Cellular senescence is defined as a state of permanent cell cycle arrest, providing a natural barrier against cancer. However, senescent cells are very metabolically active and secrete a complex mixture of bioactive molecules collectively known as the senescence-associated secretory phenotype (SASP), which play a dual role in cancer biology. While the SASP can suppress tumors by facilitating immunosurveillance, it can also promote tumor progression by fostering a pro-inflammatory milieu, stimulating angiogenesis, enhancing invasiveness, and enabling immune evasion. In Head and Neck Cancers (HNCs), a highly heterogeneous group of malignancies, SASP has emerged as a critical player in disease progression and treatment resistance. Persistent DNA damage response (DDR) signaling drives SASP and thereby contributes to the progression of head and neck cancer by modulating the tumour microenvironment. It influences the tumor microenvironment (TME) by facilitating epithelial-to-mesenchymal transition (EMT), promoting cancer stem cell-like properties, and impairing the efficacy of radiotherapy, chemotherapy, and immune checkpoint inhibitors. These effects underscore the need for targeted interventions to regulate SASP activity. This review presents a comprehensive overview of the molecular mechanisms underlying SASP generation and its effects on HNCs. We discuss the dual roles of SASP in tumor suppression and progression, its contribution to therapy resistance, and emerging therapeutic strategies, including novel senolytic and senomorphic drugs. Finally, we highlight key challenges and future directions for translating SASP-targeted therapies into clinical practice, emphasizing the need for biomarker discovery, and a deeper understanding of SASP heterogeneity. By targeting the SASP, there is potential to enhance therapeutic outcomes and improve the management of HNCs.
细胞衰老被定义为一种永久性的细胞周期停滞状态，构成抵御癌症的天然屏障。然而，衰老细胞代谢活性极高，会分泌由多种生物活性分子组成的复杂混合物，统称为衰老相关分泌表型（SASP），其在癌症生物学中具有双重作用。SASP一方面可通过促进免疫监视抑制肿瘤，另一方面也能通过营造促炎微环境、刺激血管生成、增强侵袭能力及促进免疫逃逸来推动肿瘤进展。在高度异质性的头颈部癌症中，SASP已成为疾病进展和治疗抵抗的关键驱动因素。持续的DNA损伤反应信号驱动SASP形成，并通过调控肿瘤微环境促进头颈部癌症发展。具体而言，SASP通过促进上皮-间质转化、增强肿瘤干细胞样特性、削弱放疗/化疗及免疫检查点抑制剂疗效等方式影响肿瘤微环境。这些效应凸显了靶向调控SASP活性的必要性。本综述系统阐述了SASP产生的分子机制及其对头颈部癌症的影响，探讨了SASP在抑癌与促癌中的双重作用、介导治疗抵抗的机制，以及包括新型衰老细胞清除剂和衰老表型调节剂在内的新兴治疗策略。最后，我们重点分析了SASP靶向治疗临床转化面临的关键挑战与未来方向，强调生物标志物发现及深入解析SASP异质性的重要性。通过靶向干预SASP，有望提升头颈部癌症治疗效果并改善疾病管理。
肿瘤(癌症)患者之家