Lung cancer is the most lethal type of cancer in the US. Almost all patients treated with EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, eventually develop acquired resistance. Natural Killer T (NKT) cells are being combined with EGFR TKIs in ongoing clinical trials to overcome resistance, but it is unclear whether there are synergistic effects. We hypothesized that EGFR TKIs block the production of immunosuppressive factors, including vascular endothelial growth factor (VEGF), by lung cancers and sensitizes them to NKT cell-mediated killing. We treated 2D monolayer and 3D spheroid cultures of A549 lung cancer cells with cisplatin, gefitinib, and erlotinib and measured killing and VEGF secretion. We found that EGFR TKIs reduce production of VEGF, combining EGFR TKIs with chemotherapy increases cytolysis, and adding NKT cells further enhances tumor cell death. These studies suggest that combining EGFR TKIs with immune modulation has therapeutic potential in lung cancer.