Lung cancer is the most lethal and second most diagnosed type of cancer in American men and women in 2022, and non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases. Epidermal growth factor receptor (EGFR) mutation is the second most common mutation, after KRAS, in NSCLC, and most patients with EGFR mutant lung cancers will eventually develop acquired resistance to EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. Novel therapeutic strategies, such as targeted therapy in combination with immunotherapy, are being developed to overcome resistance in NSCLC patients. For example, Natural Killer T (NKT) cells are being combined with EGFR TKIs in ongoing clinical trials, but it is unclear whether there are synergistic effects. We tested the hypothesis that treatment with EGFR TKIs blocks the production of immunosuppressive factors by lung cancers and sensitizes the cancer cells to NKT cell-mediated killing. A549, a NSCLC adenocarcinoma cell line, was treated with increasing concentrations of cisplatin, gefitinib, and erlotinib. We then measured the levels of vascular endothelial growth factor (VEGF), a potent immunosuppressant, and killing of 2D monolayer and 3D spheroid cultures. We also assessed NKT cell-mediated cytotoxicity in the presence and absence of immune checkpoint blockade. We found that treatment with EGFR TKIs reduces production of VEGF. We also found that combining EGFR TKIs with chemotherapy induces cytolysis, and the addition of NKT cells further enhances tumor cell death. Ultimately, these findings suggest that the combination of EGFR TKIs with immune modulation has therapeutic potential in lung cancer