Immunosenescence: unraveling the impact on cancer immunotherapy in the aging population

As global populations age, older adults constitute the majority of cancer patients. Their response to immunotherapy is heavily influenced by immunosenescence, a systemic remodeling of both innate and adaptive immunity with aging. Although age-related immune decline theoretically impairs antitumor responses, clinical data frequently show that older patients derive survival benefits comparable to younger cohorts. This review examines this paradox by analyzing how the aged immune system acts as a double-edged sword. We discuss how a constricted naive T cell repertoire and a suppressive tumor microenvironment create barriers, while the accumulation of antigen-experienced, exhausted T cells provides a vast reservoir for checkpoint blockade reinvigoration. We also delineate the unique clinical safety profile in this demographic, examining how localized tissue aging drives organ-specific immune-related adverse events. Beyond immune checkpoint inhibitors (ICIs), we evaluate the distinct biological barriers immunosenescence creates for chimeric antigen receptor T cell therapy, cancer vaccines, and oncolytic viruses. Finally, we propose a transition toward precision geriatric immuno-oncology. This framework relies on biological age rather than chronological age, combining comprehensive geriatric assessment with multi-omics biomarkers to promisingly define an individual's immunological age. We emphasize the potential of novel interventions, including senolytics and mitochondria-targeted platforms, to reverse immune exhaustion and optimize treatment efficacy for this growing demographic.