Frailty of older patients is not reflected in the melanoma tumor microenvironment and treatment response to immune checkpoint blockade therapy.

Older adults with frailty demonstrate systemic immunosenescence, including T-cell exhaustion and reduced immune diversity, yet maintain immune checkpoint blockade (ICB) efficacy comparable to that of younger patients. Baseline immune cell composition in both the tumor microenvironment (TME) and peripheral blood has been linked to ICB response in melanoma. To address this paradox, we investigated whether frailty is associated with alterations in the TME immune composition in melanoma.We applied imaging mass cytometry with a 40-marker panel to comprehensively characterize the pretreatment immune TME in formalin-fixed, paraffin-embedded tissue from 23 patients with melanoma, stratified by age, frailty status (as determined by the Clinical Frailty Scale), and clinical benefit from ICB. 33 immune cell phenotypes were identified and compared across patient groups.Frail patients exhibited significantly higher densities of CD4+CD45RO+ memory T cells compared with non-frail older patients. No other differences in the immune TME were observed between frail and non-frail patients, and overall survival was comparable between these groups. In contrast, multiple age-related differences were observed, including reduced naive T-cell densities and increased myeloid cell infiltration in older patients, consistent with features of immunologic aging. Clinical benefit from ICB was associated with greater overall immune infiltration and lower granulocyte densities, independent of age or frailty status.Despite previously demonstrated systemic immunosenescence, the melanoma immune TME preserved in older adults with frailty, consistent with observed preservation of ICB efficacy.