3D models to study therapy-induced senescence: where do we stand now?

Cellular senescence (CS) is a crucial tumor-suppressive phenomenon, inhibiting proliferation of cancerous cells. However, cancer therapies can also induce tumor cell senescence, generating senescent cells in tumoral and normal tissues. While initially beneficial, these senescent cells can paradoxically contribute to tumor recurrence, metastasis, and therapy resistance via the senescence-associated secretory phenotype (SASP). Due to the diverse and critical roles, cellular senescence could be a potential target in cancer biomedicine. To extend our understanding of therapy-induced senescence (TIS), developing experimental models is necessary. Currently TIS established models can be categorized into animal-based and laboratory models. These models are essential for advancing our knowledge of aging mechanisms and developing new treatment modalities. In vivo models of TIS have faced limitations, including poor immune system representation, oversimplified stromal complexity, and an inability to model functional vascular networks. Incorporating cutting-edge technologies such as 3D cultures, co-culturing, and tissue engineering can help researchers in creating in vitro models that closely mimic physiologically conditions. This review highlighted the current TIS challenges and advanced senotherapeutics. Finally, we discussed how to develop reliable in vitro models to better understanding TIS mechanisms.