Mevalonate Blockade in Cancer Cells Triggers CLEC9A⁺ Dendritic Cell-Mediated Antitumor Immunity

Area of Science:

• Immunology
• Metabolic pathways
• Cancer biology

Background:

• Hyperactive mevalonate (MVA) metabolism is common in cancer, inhibiting tumor growth and enhancing immunogenicity.
• The precise mechanisms by which MVA pathway blockade promotes antitumor immunity are not fully understood.

Purpose of the Study:

• To elucidate how blocking the MVA metabolic pathway in tumor cells stimulates antitumor immune responses.

Main Methods:

• Inhibition of the MVA metabolic pathway or Rac1 knockdown in tumor cells.
• Assessment of tumor recognition and antigen cross-presentation by dendritic cells.
• Evaluation of CD8+ T-cell-mediated antitumor immunity in immunocompetent and Batf3-/- mice.

Main Results:

• MVA pathway inhibition in tumor cells leads to type 1 classical dendritic cell (cDC1)-mediated tumor recognition and antigen cross-presentation.
• Mechanistically, MVA blockade disrupts Rac1 prenylation, exposing actin filaments recognized by CLEC9A on cDC1s, which activates antitumor T cells.
• MVA pathway blockade or Rac1 knockdown induced CD8+ T-cell-mediated immunity in immunocompetent mice but not in mice lacking cDC1s.

Conclusions:

• Tumor MVA metabolic blockade activates a cDC1 response via CLEC9A-mediated recognition of tumor cytoskeleton, revealing a novel immune surveillance mechanism.
• Dendritic cells monitor tumor metabolic dysregulation, and MVA pathway inhibition can be leveraged to potentiate anticancer immunity.