In their recent work published in Cell Metabolism, PhD candidate Sophie Poznanski and Dr. Ali Ashkar demonstrate that immune cell metabolism is a central factor in determining NK cell inhibition or cytotoxic function in the tumor microenvironment (TME).

 

Over the last decade, NK cells have garnered attention as a highly promising candidate for cancer immunotherapy due to their high tumor killing capacity and intrinsic ability to distinguish between healthy and malignant cells. Cytotoxic NK cells primarily rely on glucose-driven glycolysis and oxidative phosphorylation to fuel their anti-tumor functions. However, the immunosuppressive TME of solid tumors is metabolically hostile, as tumors require extensive nutrient uptake to support their rapid proliferation. This nutrient deprivation has been linked to impaired anti-tumor function and may be yet another hurdle preventing the success of NK cell immunotherapy against solid tumors.  

 

To investigate the impact of the TME on NK cell metabolism, Poznanski et al. assessed the anti-tumor functions and metabolic capacity of tumor associated NK (taNK) cells from ovarian cancer patients and peripheral blood NK (pbNK) cells in an ex vivo model of the TME. The authors show that not only do taNK cells and TME-exposed pbNK cells have significantly impaired anti-tumor functions, but they also have drastically reduced glycolysis and oxidative phosphorylation. Proteomic analysis of TME-exposed pbNK cells demonstrated an impaired ability to repair DNA damage due to oxidative stress. Targeting oxidative stress with RTA-408, an activator of Nrf2 antioxidant activity, rescued metabolic inhibition in the TME and restored NK cell activity in vivo, resulting in complete ablation of tumor growth. Thus, the TME induces oxidative damage and disrupts metabolic pathways that are required for NK cell anti-tumor function.

 

Previous works by the Ashkar lab have established the anti-tumor efficacy of ex vivo expanded NK cells (expNK) against large, established tumors in mice. Through further investigation, Poznanski et al. revealed that the secret to expNK cell anti-tumor potency is their acquisition of the classic Warburg metabolism used by tumor cells. This metabolic reprogramming better equips expNK cells for the TME, as they not only resist suppression, but show enhanced tumor killing in the hostile TME. While pbNK cells exhibit a strict dependency on certain fuel sources to meet their energetic needs, Poznanski et al. show that expNK cells are metabolically flexible and can use any fuel source to reach their energetic capacity. Thus, expNK cells can efficiently adapt their metabolism to fit their environment, similar to tumor cells, allowing them to thrive in the TME.

 

Altogether, the results of this work highlight metabolism as a critical factor that defines NK cell success in the TME and demonstrates its potential as a therapeutic target for cancer immunotherapy against solid tumors.