Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths worldwide. Despite advances in treatment options, conventional chemotherapy remains a pivotal part of NSCLC treatment, regardless of stage, even though it is accompanied with serious side effects and therapy-induced senescence (TIS). Cellular senescence is a durable cell cycle arrest and is characterized by the secretion of a strong pro-inflammatory senescence-associated secretory phenotype (SASP). Evidence indicates that TIS induces deleterious long-term effects including disease progression, metastasis and recurrence. Thus, TIS acts as a barrier to complete eradication of the tumor, indicating the importance of targeting senescent cells during cancer therapy. Therefore, I will investigate a novel combination treatment in this project, specifically designed to eliminate therapy-induced senescent cells. Senescent tumor cells will be targeted by two strategies: senolytics to specifically kill these cells and senostatics to suppress or modulate the SASP. Moreover, I will identify the core senescent secretory profile of NSCLC, that will be used as a blood-based biomarker to identify and select patients that would benefit from our new senescence-focused therapy. The successful completion of my project will ultimately improve overall survival of NSCLC patients with a tumoral senescence signature, regardless of stage, by enhancing treatment efficacy and preventing relapse.