Brain metastasis occurs when cancer cells spread to the brain, where the immunosuppressive environment and unique metabolic demands complicate treatment. Aging exacerbates these challenges by altering the tumor microenvironment, affecting nutrient availability, inflammation, and immune function. These age-related changes can influence metastatic progression, highlighting aging as a critical but often overlooked factor in brain metastasis. A fundamental question to address is how aging impacts the metabolic fitness of immune cells and how these changes negatively affect the progression of brain metastasis. We hypothesize that the decline in immune activity during aging is caused by dysregulated metabolism. Therefore, restoring the metabolic fitness of immune cells would be highly beneficial in enhancing their ability to suppress brain metastasis.

To further investigate this, we developed a model featuring specific ablation of mitochondrial complex III in microglia by crossing Uqcrq floxed and Tmem119-cre/ERT2 mice (referred to as QPC KO). This model demonstrated that mice with ETC-deficient microglia developed larger brain metastases. We propose to utilize this newly generated mouse model, which mimics the effects of aging through deficient mitochondrial metabolism in microglia, to examine the role of mitochondrial metabolism in the anti-tumor function of microglia. Our aim is to elucidate how and why these processes are impaired with age.

Our preliminary data, obtained from RNA-seq analysis of tumor-associated and resting microglia in young and old mice, revealed significant differences in microglial activation between the two age groups. Notably, pathways related to mitochondrial oxidative metabolism were particularly impaired with age.

These findings suggest that mitochondrial metabolism is crucial for microglial activation and anti-tumor function, while aging hinders these adaptive mechanisms.