NPC1L1 on pancreatic adenocarcinoma cell functions as a two-pronged checkpoint against antitumor activity

Pancreatic adenocarcinoma (PAAD) is a highly lethal malignancy with an immunosuppressive microenvironment and a limited immunotherapy response. Cholesterol is necessary for rapid growth of cancer cells, and cholesterol metabolism reprogramming is a hallmark of PAAD. How PAAD cells initiate cholesterol reprogramming to sustain their growth demand and suppressive immunomicroenvironment remains elusive. In this study, we for the first time revealed that PAAD cells overcome cholesterol shortage and immune surveillance via ectopically overexpressing NPC1L1, a cholesterol transporter, but function as a two-pronged checkpoint, which not only directly suppresses TCR activation of CD8⁺T cells but also hijacks the intracellular cholesterol from CD8⁺T cells. In vivo, we showed that ezetimibe, an NPC1L1 inhibitor usually for hypercholesterolemia, efficiently prevented PAAD cells from depriving cholesterol of CD8⁺T cells, and improved the anti-tumor immunity of PAAD to synergize with PD-1 blockade, suggesting NPC1L1 as a promising target to rescue the anti-tumor activity in PAAD.