Age-related immune states and PD-1 blockade: mechanisms and strategies for the elderly

Aging impairs antitumor immunity and may reduce the efficacy of immune checkpoint inhibitors (ICIs). However, the underlying mechanisms remain unclear. Building on our recent findings, we review three key mechanisms of CD8⁺ T-cell aging: elevated T-cell receptor (TCR) activation thresholds, mitochondrial dysfunction, and disruption of proteostasis. Studies in aged mice have revealed that aged naïve T cells exhibit defective priming due to increased CD45 expression, which raises the TCR activation threshold and restricts effector differentiation. Aging also impairs mitochondrial metabolism, particularly fatty acid oxidation. Furthermore, we highlight the role of proteostasis collapse, including defective autophagy and increased endoplasmic reticulum stress, as a contributor to T-cell dysfunction. Spermidine, a polyamine that declines with age, has the potential to modulate both mitochondrial function and proteostasis. Its supplementation has been shown to improve programmed cell death-1 blockade responsiveness in aged mice. Although clinical studies in humans have yielded inconsistent results regarding the effect of chronological age on ICI efficacy, identifying patients with "age-related" immune microenvironments may enable stratified therapeutic approaches based on insights from preclinical aging models.