Tumor-Associated Immunosenescence: Mechanisms, Biomarkers, and Age-Adaptive Immunotherapy

Immunosenescence alters immune-cell composition, signaling, metabolism, and regenerative capacity, but chronological age alone does not reliably predict response to cancer immunotherapy. In older adults, thymic involution, hematopoietic remodeling, inflammaging, and the accumulation of dysfunctional lymphoid and myeloid populations interact with tumor-derived suppressive signals. We organize these processes within an Immunosenescence-Immunotherapy Interference Axis linking systemic immune aging, local tumor remodeling, and treatment-specific vulnerabilities. Evidence is reviewed for senescence-like and exhausted CD8+ T cells, NK-cell dysfunction, age-associated macrophage states, loss of T-cell receptor diversity, and their relationship to immune checkpoint blockade. We then assess blood, tissue, and single-cell biomarkers that may distinguish biological immune age from chronological age, with particular attention to the limitations of single-marker classification. Finally, we critically evaluate senolytics, cytokine support, co-stimulatory approaches, and metabolic modulation as potential adjuncts to immunotherapy. The available evidence supports biomarker-informed, age-adaptive trial design, but prospective validation is required before immune-rejuvenation strategies can be recommended in routine oncology.