Tumor cell AMPK activation enhances NK cell anti-tumor immunity and synergizes with PD-L1 blockade therapy.

Immune checkpoint blockade targeting the programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) pathway has shown great clinical results, but only in a small subpopulation of cancer patients. The underlying mechanism of resistance to immune checkpoint therapy remains largely elusive. AMP-activated protein kinase (AMPK) senses metabolic stress, restores energy balance, and plays important roles in tumorigenesis. Here, we report that tumor cell-intrinsic AMPK activation dictates the sensitivity of tumor cells to PD-L1 immunotherapy and natural killer (NK) cell-mediated anti-tumor immunity. PD-L1 checkpoint blockade resulted in increased phosphorylation of AMPK in anti-PD-L1-responsive but not -nonresponsive tumors. Pharmacological inhibition of AMPK activation diminished the therapeutic effect of PD-L1 checkpoint blockade. Conversely, pharmacological or genetic activation of AMPK in cancer cells sensitized them to NK cell-mediated killing through perforin and synergized with PD-L1 blockade therapy to suppress tumor growth in mice in an NK cell-dependent manner. Transcriptomic analyses revealed that AMPK activation in tumor cells triggered the expression of pattern recognition receptor genes and a chemokine gene expression signature that is associated with longer overall survival of cancer patients. These findings indicate that AMPK controls tumor responsiveness to checkpoint blockade therapy through NK cell-dependent mechanisms.