Wang and Matosevic review how the solid tumor microenvironment (TME) impairs NK cell infiltration, metabolism, and effector functions, and consider strategies to reverse these effects. The heterogeneous and multi-dimensional TME contains suppressive cells (Tregs, MDSCs, and fibroblasts), checkpoint pathways (NKG2A/HLA-E, PD-1/PD-L1, and TIGIT/CD155), and soluble factors (TGF-β, adenosine, lactate, and PGE2). NK cell antitumor activity can be supported by targeting the above pathways through antibody therapies, small molecule inhibitors, or cytokine support, or by engineering chemokine and CAR receptors on NK cells.
Contributed by Alex Najibi
BACKGROUND: The unique ability of NK cells to target cancer cells without antigen specificity makes them an attractive prospect for immunotherapy of solid tumors. However, the complexity of the tumor microenvironment (TME), particularly its heterogeneity and associated immunosuppressive properties, enables solid tumor cells to escape NK cell immune-surveillance by impairing their infiltration and cytotoxic functions. As a result, NK cells that have been able to infiltrate solid tumors are dysfunctional, exhausted and metabolically and functionally impaired. Understanding the status of NK cells in solid tumors and the interplay between the tumor-promoting functions of the TME and the immunometabolic reprogramming events that NK cells endure as a result is essential to developing approaches to improve the clinical outcome of NK cell-based immunotherapies against solid tumors. CONCLUSIONS: In this review, we address the current knowledge on the presence and immunometabolic roles of NK cells in solid tumors as well as the strategies developed to restore NK cell activities in these conditions, with the ultimate goal of enhancing persistence, trafficking, cytotoxicity and metabolic functions.
Author Info: (1) Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, IN, 47907, USA. (2) Department of Industrial and Physical Pharmacy, Purdue University, West L
Author Info: (1) Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, IN, 47907, USA. (2) Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, IN, 47907, USA. sandro@purdue.edu. Center for Cancer Research, Purdue University, West Lafayette, IN, 47906, USA. sandro@purdue.edu.
