Immunosenescence and Cancer: Cellular Aging Programs That Reshape Antitumor Immunity.

Abstract

Immunosenescence refers to the age-associated decline in immune competence, driven, in part, by the senescence-associated secretory phenotype (SASP), which maintains chronic low-grade inflammation ("inflammaging"). Aging alters both innate and adaptive immunity, marked by impaired phagocytosis, antigen presentation, and cytotoxicity in macrophages, dendritic cells, neutrophils, and NK cells, as well as dysfunctional B-cell subsets, thymic involution, reduced TCR diversity, and accumulation of senescent CD4⁺CD28^- and CD8⁺CD57⁺KLRG1⁺ T cells. Within tumors, these alterations promote immune evasion through SASP-derived IL-6 and TGF-β, expand myeloid-derived suppressor cells, and favor angiogenic and immunosuppressive macrophage states. Cytotoxic lymphocyte and NK-cell dysfunction further weakens antitumor immunity and limits the responses to checkpoint inhibitors and chimeric Ag receptor T-cell therapy in older patients. In this review, we summarize the cellular and molecular mechanisms underlying immune cell aging and outline how immunosenescence programs reshape the tumor microenvironment and influence cancer immunotherapy outcomes.