Tumor Cholesterol Blocks PD-L1 Destruction to Escape Immune Attack

Cancer cells are well-known to over-produce cholesterol, but why this helps tumors evade the immune system has remained unclear. This study from the Department of Dermatology at Fourth Military Medical University used bioinformatics, mouse tumor models, and mechanistic cell biology to uncover a surprising link: tumor cholesterol biosynthesis directly stabilizes the immune checkpoint protein PD-L1 by suppressing lysosomal degradation, thereby preventing CD8+ T cells from recognizing and destroying cancer cells.

The researchers began with bioinformatics analysis of The Cancer Genome Atlas (TCGA) data across multiple cancer types, finding a robust negative correlation between cholesterol biosynthesis gene expression scores and tumor-infiltrating lymphocyte (TIL) scores. Specifically in skin cutaneous melanoma (SKCM), higher expression of cholesterol synthesis genes correlated with lower immune infiltration, fewer activated CD8+ T cells, and worse patient outcomes. The HMGCR-MTOR-LAMP1 axis — a molecular trio connecting cholesterol, mTOR activity, and lysosome abundance — emerged as a predictor of poor immunotherapy response and reduced overall survival.

Mechanistically, the study demonstrated that cholesterol synthesized in tumor cells traffics to lysosomes and activates mTORC1 at the lysosomal membrane. Active mTOR phosphorylates TFEB (transcription factor EB), retaining it in the cytoplasm in an inactive state. Because TFEB is the master regulator of lysosome biogenesis, its cytoplasmic sequestration reduces lysosome numbers and activity. As a consequence, PD-L1 protein — which is normally turned over through lysosomal degradation — accumulates on the tumor cell surface, delivering suppressive signals to PD-1-expressing T cells and shutting down anti-tumor immunity.

Inhibiting cholesterol biosynthesis using the HMGCR inhibitor simvastatin, or via genetic knockdown of HMGCR, reduced lysosomal cholesterol accumulation, impaired mTORC1 activation at lysosomes, and allowed TFEB to translocate into the nucleus. Nuclear TFEB then drove transcription of lysosome biogenesis genes (including LAMP1), expanding lysosome mass and accelerating PD-L1 protein degradation. This effect was blocked by chloroquine (a lysosome inhibitor) or ATG5 knockdown, confirming the lysosomal/autophagic route of PD-L1 clearance. The reduction in surface PD-L1 substantially enhanced CD8+ T cell infiltration, IFNG (IFN-γ) and granzyme B expression, and tumor killing in co-culture and mouse xenograft models.

In mouse melanoma models, HMGCR inhibition combined with anti-PD-1 checkpoint blockade produced synergistic tumor growth suppression compared with either treatment alone, with markedly increased intratumoral CD8+ T cell density. Patient data from melanoma cohorts corroborated these findings: high HMGCR and high LAMP1 expression (indicating active mTOR and low lysosome turnover) predicted significantly worse response to anti-PD-1 immunotherapy and worse overall survival. These data present a compelling rationale for clinical trials combining statins or other cholesterol synthesis inhibitors with immune checkpoint blockade across multiple cancer types.