Cisplatin remains the most effective therapy for non-small cell lung cancer (NSCLC). We previously have found cisplatin-resistant lung cancer cells (A549CisR and H157CisR) were more resistant to natural killer (NK) cell-mediated cytotoxicity than parental cells. We also discovered that fatty acid synthase (FASN) levels in cisplatin-resistant cells were significantly higher than in parental cells. To reveal whether a link exists between the up regulated FASN levels and higher resistance to NK cell cytotoxicity, we performed inhibition studies using a FASN inhibitor and applied the FASN knockdown approach. In both approaches, we found that the FASN inhibition/knockdown significantly increased the susceptibility of cisplatin-resistant cells to NK cell cytotoxicity. We further found such decreased susceptibility was associated with an increased programmed death receptor ligand (PD-L1) level in cisplatin-resistant cells. In mechanisms studies, TGF-beta 1 was found to be the FASN downstream signaling molecule that was responsible for modulating the PD-L1 levels in cisplatin-resistant cells. Accordingly, TGF-beta 1 inhibition resulted in significantly increased susceptibility of cisplatin-resistant cells to NK cell cytotoxicity. We suggest that the inhibition of FASN-TGF beta 1-PD-L1 axis may improve the efficacy of immunotherapy in treating cisplatin-resistant lung cancer.