Immunotherapy for senescent cell clearance: Hallmarks, strategies and translational challenges

Cellular senescence, a complex multifactorial process, is involved in the pathophysiology of various age-related diseases, such as cardiovascular disease and neurodegenerative disorders. Traditional interventions targeting single mechanisms yield limited efficacy. As a core hallmark and driver of aging, immunosenescence provides a critical target for precision interventions. This systematic review examines the hallmarks of aging, including cellular damage, epigenetic abnormalities, and immunosenescence. It highlights immunotherapy strategies targeting senescent cells, including CAR-T/NK cell therapies, vaccines, and immune checkpoint blockade. These approaches have demonstrated significant efficacy in animal models by eliminating senescent cells and improving senescence phenotypes. Simultaneously, it analyzes current challenges such as insufficient target specificity, safety and cost concerns in cell therapies, and species differences. It also explores future directions including multi-target synergistic strategies, AI-assisted target screening, and the integration of precision medicine technologies. Immunotherapy offers a revolutionary paradigm for aging intervention, holding promise to extend healthy lifespan by regulating the immune system. However, further breakthroughs are needed for its clinical translation.