Atorvastatin pre-exposure in hypercholesterolemia remedies 27HC mediated dendritic cell dysfunctions in triple-negative breast cancer

Early inception of hypercholesterolemia has led to prevalent statin pre-exposure among cancer patients. Furthermore, emerging associations between increased circulating cholesterol, dyslipidemia, and cancer recurrence have spurred the repurposing of statins to combat cancer. However, the mechanistic impact of statin pre-exposure on cancer progression remains unclear. Here, our retrospective study with triple-negative breast cancer (TNBC) patients showed that atorvastatin pre-exposure promotes recurrence-free survival. Atorvastatin pre-exposure in TNBC patients and a preclinical high-fat diet-induced hypercholesterolemic murine tumor model lowered intratumoral 27-hydroxycholesterol (27HC) concentration, as estimated by LC-MS/MS. Within the tumor microenvironment, elevated 27HC interacted with estrogen receptor alpha (ERα) on dendritic cells (DCs), hindering DC maturation, migration, and antigen presentation. Atorvastatin reduced ERα expression on DCs and remediated 27HC-ERα-induced DC dysfunctions, improved DC-mediated T cell priming, thereby facilitating tumor restriction when adoptively transferred to 4T1-bearing NOD/SCID/IL2Rγ−/− mice. Targeted intratumoral knockdown of cyp27a1 (rate-determining enzyme for 27HC production) alongside atorvastatin pre-exposure uplifted cDC1 functionality. Atorvastatin pre-treatment exerts its action by reducing the availability of intratumoral 27HC and expression of ERα on DCs, which eventually enhances DC functionality and restores their efficiency to prime anti-tumor CD8+ T cell responses. Therefore, atorvastatin pre-exposure adjunct to 27HC-ERα inhibition may serve as an effective immunotherapeutic intervention in TNBC.