Abstract
Breast and other solid tumors respond poorly to immune therapy. Myeloid cells (MCs) such as macrophages contribute to resistance. Established clinical evidence links cholesterol to cancer outcomes, with MC function being regulated by cholesterol metabolism. We screened MC-expressed regulators of cholesterol homeostasis linked to survival and identified the cholesterol efflux protein ABCA1. ABCA1 activity increases anticancer functions of macrophages: enhancing tumor infiltration, decreasing angiogenic potential, reducing efferocytosis, and improving support of CD8+ T cell activity. Mechanistically, different AKT isoforms are involved, through both PI3K-dependent and PI3K-independent mechanisms. Highlighting the clinical relevance of our findings are correlations between ABCA1 in macrophages and angiogenic potential, VEGFA, and CD8 T cell abundance and activity. The culmination of these activities was demonstrated through increased tumor growth and metastasis in mice lacking MC-expressed ABCA1. Tumors grown in these mice were also more resistant to immune therapy. Therefore, modulating ABCA1 activity within MCs may represent a previously unidentified approach to immune therapy.