Article Figures & Data
Figures
- Figure 1
Summary of various approaches to targeting NK cell dysfunction and enhancing NK cell effector function. ① Activating immune checkpoints. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), Fas ligand (FasL), and NKG2D are activating immune checkpoints expressed on NK cells that can trigger cytotoxicity. Inducing the expression of these molecules and their ligands can restore the antitumor effects of NK cells and make tumor cells more susceptible to immune destruction. ② Targeting aberrant metabolism of NK cells in the tumor microenvironment (TME). TGF-β, FBP1, and a hypoxic TME elicit NK cell dysfunction by impairing mitochondrial homeostasis, metabolism, and viability. Additionally, the sphingomyelin (SM) content and the surface topology of NK cells are often abnormal in the TME. Wei’s group has found that therapeutically targeting TGF-β signaling, FBP1, or sphingomyelinase with blocking monoclonal antibodies or small molecule inhibitors restores NK cell antitumor activity in the immunosuppressive TME. ③ Targeting inhibitory immune checkpoints. Inhibition of NK cell inhibitory receptor signaling with anti-NKG2A (monalizumab), anti-PD-1 (pembrolizumab), anti-TIGIT (tiragolumab), or anti-KIR (lirilumab) enhances NK cell cytotoxicity and the antitumor response.
