NK cells in the tumor microenvironment and thioredoxin activity.

NK cells are responsible for defense against viral infections and cancer. Although activated NK cells are armed to combat tumors, the tumor microenvironment (TME) contains ROS, which suppress NK cell antitumor activity. In this issue of the JCI, Yang, Neo, and colleagues explored NK cell resistance to oxidative stress in vitro and in human non-small-cell lung cancer (NSCLC). High surface thiol density and elevated expression of the ROS scavenger thioredoxin (Trx1) protected NK cells from ROS. Trx1 and thiol levels were higher in IL-15- than in IL-2-primed NK cells. Tumor-infiltrating Trx1+ NK cells were present in patients with NSCLC with elevated ROS levels in the tumor. Smokers scored higher for the ROS signature, which predicted poor prognosis, compared with nonsmokers. This study explains how activated NK cells survive in the ROS-rich TME and suggests that smokers with lung cancer may benefit from therapies using IL-15-primed NK cells.