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Simple Summary: Therapies targeting TIGIT have garnered tremendous interest, but have so far failed to reach primary endpoints in PhIII trials in lung cancer settings. This study examined the function of TIGIT on NK cells and how NK cells may impact the success of TIGIT therapeutics. This study demonstrated that TIGIT expression is increased on activated NK cells, including those expanded with clinical protocols for cell therapy. Activated TIGIT+ NK cells have a better anti-tumor response as compared to TIGIT− NK cells. More importantly, higher tumor infiltration of activated NK cells correlates with better patient outcomes in lung adenocarcinoma. However, chronic TIGIT engagement with its ligands in the tumor microenvironment leads to the functional decline of NK cells, which can be prevented with anti-TIGIT. This demonstrates that TIGIT-expressing cells are not inherently exhausted but can represent NK cells with the highest anti-tumor activity. These findings support the joint application of NK cells with blocking, non-depleting anti-TIGIT for improved treatment outcomes. Treatments targeting TIGIT have gained a lot of attention due to strong preclinical and early clinical results, particularly with anti-PD-(L)1 therapeutics. However, this combination has failed to meet progression-free survival endpoints in phase III trials. Most of our understanding of TIGIT comes from studies of T cell function. Yet, this inhibitory receptor is often upregulated to the same, or higher, extent on NK cells in cancers. Studies in murine models have demonstrated that TIGIT inhibits NK cells and promotes exhaustion, with its effects on tumor control also being dependent on NK cells. However, there are limited studies assessing the role of TIGIT on the function of human NK cells (hNK), particularly in lung cancer. Most studies used NK cell lines or tested TIGIT blockade to reactivate exhausted cells obtained from cancer patients. For therapeutic advancement, a better understanding of TIGIT in the context of activated hNK cells is crucial, which is different than exhausted NK cells, and critical in the context of adoptive NK cell therapeutics that may be combined with TIGIT blockade. In this study, the effect of TIGIT blockade on the anti-tumor activities of human ex vivo-expanded NK cells was evaluated in vitro in the context of lung cancer. TIGIT expression was higher on activated and/or expanded NK cells compared to resting NK cells. More TIGIT+ NK cells expressed major activating receptors and exerted anti-tumor response as compared to TIGIT− cells, indicating that NK cells with greater anti-tumor function express more TIGIT. However, long-term TIGIT engagement upon exposure to PVR+ tumors downregulated the cytotoxic function of expanded NK cells while the inclusion of TIGIT blockade increased cytotoxicity, restored the effector functions against PVR-positive targets, and upregulated immune inflammation-related gene sets. These combined results indicate that TIGIT blockade can preserve the activation state of NK cells during exposure to PVR+ tumors. These results support the notion that a functional NK cell compartment is critical for anti-tumor response and anti-TIGIT/adoptive NK cell combinations have the potential to improve outcomes. [ABSTRACT FROM AUTHOR]