The dual role of senescent tumor-infiltrating immune cells: a review of cancer immunotherapy strategies
The dual nature of immunosenescence
Immunosenescence, the decline in immune function with age, has been viewed as a process that weakens immune surveillance and increases cancer risk. In the tumor microenvironment, however, senescent immune cells can either support or suppress cancer, depending on the context. This review, published in Critical Reviews in Oncology/Hematology, summarizes existing research, focusing on tumor-infiltrating T cells, natural killer (NK) cells, and macrophages. It does not report a new clinical trial testing treatment efficacy.
Mechanisms behind the dual role
The review discusses DNA damage, epigenetic remodeling, metabolic reprogramming, and major signaling pathways as mechanisms that drive immune-cell senescence. The senescence-associated secretory phenotype (SASP) and immunosuppressive phenotypes can promote chronic inflammation, immune evasion, and remodeling of the stroma surrounding tumors, thereby supporting tumor development and progression. Here, an immunosuppressive phenotype refers to cellular characteristics that suppress immune responses.
Conversely, the authors explain that, under certain stimuli, some populations of senescent immune cells may retain or enhance their effector functions and contribute to antitumor immunity. This means that senescent immune cells do not all act in the same direction. However, the provided abstract does not specify the stimulus conditions or experimental models for each cell type, so it is difficult to establish precisely under which conditions antitumor function is enhanced.
Immunotherapy and emerging strategies
The authors examine how immunosenescence affects the efficacy of major immunotherapies and discuss gene editing and metabolic interventions as emerging strategies to improve cancer immunotherapy in older patients. The abstract alone does not support the conclusion that existing immunotherapies are generally less effective in older patients. Nor does it report clinical results showing that the proposed interventions improved treatment efficacy in patients.
The dual nature of immunosenescence provides a reason to consider both harmful immunosuppressive effects and remaining antitumor functions when evaluating treatment strategies. Application in clinical care requires further research to establish differences across cell populations and tumor environments and assess the efficacy and safety of interventions. Improvements in treatment regardless of age or the elimination of age-related disparities in cancer treatment are not outcomes demonstrated by this review.
Source: Review citation and abstract.
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.
Treating all senescent immune cells as harmful could overlook antitumor functions retained by some of them. The review’s practical significance lies in a research direction: when evaluating strategies that target immunosenescence, researchers should consider both reducing immunosuppression and preserving antitumor function. For example, follow-up studies evaluating candidate gene-editing or metabolic interventions could examine whether functional changes in specific cell populations favor tumor suppression. This is a research implication drawn from the review. The provided abstract offers no patient-selection criteria for clinical use or data with which to assess the efficacy and safety of these interventions, so it cannot be applied directly as a basis for changing treatment choices for older patients.