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Lung cancer is one of the leading causes of death in the world and curative treatments are still lacking for most patients. Immunotherapeutic approaches in lung cancer patients focus on immune checkpoint receptors, but usually do not cure the patient per se, and combinatorial approaches are required to increase survival. Natural Killer (NK) cells, part of the innate immune response, are well known for their ability to kill tumor cells. We propose that so-called "adaptive tissue-resident NK cells" are particularly suitable for infiltrating lung tumors and could be exploited to treat lung tumors in future therapeutic strategies. To study the potential of adaptive tissue-resident NK cells in cancer therapies, we will collect lung tumors from lung cancer patients and perform a spatial analysis of the different regions of the tumors (distal, marginal, central) with multiparameter flow cytometry and spatial transcriptomics, providing us with data of high-dimensional quality (goal 1). In vitro-expanded NK cells (aim 2a) will be co-cultured with lung tumor target cells and 3D lung tumor models, and cytotoxicity and infiltration in these artificial tumors will be analyzed by microscopy where one can follow living cells over time (aim 2b). Here, we aim to map adaptive tissue-resident NK cells in human lung tumors, isolate and expand this NK cell population, and analyze their cytotoxicity and tumor infiltration capacity. We expect that the results will help to evaluate the applicability of adaptive tissue-resident NK cells in therapeutic approaches for lung cancer patients. My overall vision is to define new treatment strategies to complement immunotherapeutic applications in lung cancer patients and ultimately increase overall patient survival.