Immunosenescence in Aging and Cancer: Molecular Mechanisms, Tumor Microenvironment Remodeling, and Therapeutic Implications

Abstract

Immunosenescence is the decline in immune function with age, which influences cancer progression and treatment outcomes. This process arises from multiple, interconnected molecular and cellular alterations. Among these, mitochondrial dysfunction in aged immune cells may contribute to impaired immune function through altered metabolism, redox imbalance, and inflammatory signaling. This review discusses mitochondrial alterations alongside other age-related mechanisms that shape immune cell function and may promote cancer development. We examine how DNA damage, telomere shortening, epigenetic changes, altered proteostasis, and mitochondrial dysfunction contribute to immune aging and potentially compromise antitumor immunity. The aged tumor microenvironment is characterized by increased immunosuppressive cell populations, persistent inflammatory signaling, and metabolic alterations that can influence tumor development and therapeutic responses. We also examine how aging affects response to current cancer immunotherapies. While some treatments show comparable efficacy in older and younger patients, others may be less effective in the context of age-related immune dysfunction. Older patients may also experience distinct toxicity profiles that require careful clinical management. Understanding how mitochondrial alterations interact with other mechanisms of aging to shape immunosenescence may help identify therapeutic strategies for cancer in older adults. Future approaches may combine interventions targeting mitochondrial fitness, chronic inflammation, and cellular senescence. However, clinical studies specifically designed to include older populations are needed to establish the relevance of these mechanisms in cancer and to guide age-specific therapeutic strategies.