Senescence in non-cancerous cells within the tumor: What is the real deal?

Senescence is a dynamic stress response that not only enforces growth arrest in damaged cells but also profoundly reshapes the tissue microenvironment through secretory programs, immune modulation, and extracellular matrix remodeling. In the context of cancer, senescence occurs not only in malignant cells but also in non-cancerous populations, where it can actively influence tumor initiation, progression, and therapy response. This review focuses on senescent non-malignant cells within tumors, exploring how oncogene-induced senescence, therapy-induced senescence, and age-associated niches drive senescence in these compartments and remodel the tumor microenvironment. Finally, we discuss senotherapies (senolytics and senomorphics) and highlight that achieving lineage- and context-selective targeting of senescent non-malignant niches remains a key translational goal that could improve therapy response and reduce relapse.