Critical Reviews in Oncology/hematology · May 21, 2026

Bidirectional roles of senescence in tumor-infiltrating immune cells: Mechanisms, impact on immunotherapy, and therapeutic strategies

By Zhao R, Li Y, Zhu R et al.

Immunosenescence refers to the progressive functional decline of the immune system with age. Traditionally, it has been regarded as detrimental because it weakens immune surveillance and increases the risk of tumor development. With the growing understanding of the tumor microenvironment (TME), accumulating evidence indicates that the senescence of tumor-infiltrating immune cells is context-dependent and exerts bidirectional regulatory effects. On the one hand, the senescence-associated secretory phenotype (SASP) and immunosuppressive phenotypes can drive chronic inflammation, immune escape, and stromal remodeling, thereby promoting tumor initiation and progression. In contrast, subsets of senescent immune cells can retain or even acquire enhanced effector functions under specific stimuli, contributing to antitumor immune responses. This review focuses on tumor-infiltrating immune cells, particularly T cells, NK cells, and macrophages, and summarizes their senescence-associated phenotypes and dual roles in cancer development. We outline the central mechanisms by which DNA damage, epigenetic remodeling, metabolic reprogramming, and key signaling pathways drive the process of immunosenescence. We systematically examined how immunosenescence shapes the efficacy of major immunotherapies. Finally, we discuss emerging strategies, such as gene editing and metabolic interventions, to improve cancer immunotherapy in older patients.

doi.org/10.1016/j.critrevonc.2026.105385PubMed 42173209Mechanisms