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CAR-T cell therapy has emerged as a key strategy for cancer treatment. The success of CD19-directed CAR-T cells on haematological malignancies has generated a wide interest in the expansion of this approach to solid tumors. However, the clinical outcomes in this context have been unexpectedly poor due to both extrinsic and intrinsic suppressive factors that drive T cell dysfunction within the tumor microenvironment. A fundamental characteristic that contributes to anti-tumor T cell functionality and that determines CAR-T cell efficacy is the maintenance of mitochondrial fitness, which has been shown to sustain memory/stem-like properties and provide prolonged T cell responses. However, mitochondrial dysfunction is a hallmark of aging. How age-associated alterations of immune metabolism affect the outcome of CAR-T cell therapy remains poorly understood.

Here we generate Her2 …