Macrophages at the crossroads of cellular senescence and cancer development and progression: Therapeutic opportunities and challenges

Macrophages are pleiotropic immune cells essential for maintaining tissue homeostasis and modulating immune responses. Their inherent plasticity enables polarization into distinct functional phenotypes: M1 (pro-inflammatory) and M2 (anti-inflammatory), which critically influence the progression of various diseases, including cancer. Cellular senescence, a state characterized by irreversible cell cycle arrest and the secretion of pro-inflammatory factors (SASP), substantially contributes to aging and disease pathogenesis. The interaction between macrophages and senescent cells is complex: macrophages contribute to tissue integrity by clearing senescent cells to prevent tissue dysfunction, while senescent cells can alter macrophage function, influencing inflammation and cancer development. This review examines the dual roles of macrophages in cellular senescence and cancer, focusing on their capacity to both protect against and promote tumor progression. It examines how macrophages recognize and phagocytose senescent cells, the impact of macrophage dysfunction on senescence-associated pathologies, and the role of tumor-associated macrophages (TAMs) in shaping the tumor microenvironment. Key concepts to be addressed include macrophage plasticity, SASP-mediated modulation of macrophage function, and the dual role of macrophages in cancer, where they can either suppress tumor growth or promote progression via angiogenesis, immune evasion, and metastasis. The mutual interplay between macrophages and senescent cells highlights the therapeutic potential of targeting this interaction for managing age-related diseases and cancer.