Immunosenescence shapes the tumor immune microenvironment and limits PD-1/PD-L1 blockade efficacy in older patients with cancer

As the global population ages, immunosenescence is emerging as a critical determinant of cancer outcomes in older adults. Although programmed cell death protein 1/protein programmed death-ligand 1 (PD-1/PD-L1) blockade has significantly improved the treatment of multiple malignancies, its efficacy in older patients is highly heterogeneous, and the biological basis for this variability remains incompletely understood. Current evidence indicates that immunosenescence reshapes antitumour immunity through thymic involution, reduced T cell receptor diversity, chronic low-grade inflammation, and expansion of immunosuppressive cell populations, thereby impairing antigen presentation, weakening T cell activation and effector function, promoting terminal T cell exhaustion, and reinforcing suppressive tumour microenvironments. Together, these changes form an important mechanistic basis for the limited benefit of PD-1/PD-L1 blockade in older patients. Meanwhile, potentially targetable processes, including metabolic dysregulation, mitochondrial dysfunction, defective autophagy-mitophagy, redox imbalance, and gut microbiota dysbiosis, are increasingly recognized as modifiable contributors to age-associated resistance to immunotherapy. In this Review, we discuss how immunosenescence remodels antitumour immunity and constrains responses to PD-1/PD-L1 blockade in older patients, and we summarize potential strategies to improve immunotherapeutic efficacy in this population. These insights may inform future mechanistic studies, biomarker discovery, and the development of age-adapted therapeutic strategies.