Immunomodulatory Potential of KSTM in Activating Natural Killer Cells for Cancer Cell Elimination

Background/Objectives: Cancer remains a major cause of mortality worldwide, and resistance to therapy continues to limit treatment success. Improving the susceptibility of cancer cells to immune-mediated killing, particularly by natural killer (NK) cells, may enhance therapeutic outcomes. This study aimed to determine whether natural products can sensitize non-small cell lung cancer (NSCLC) cells to NK cell-mediated cytotoxicity. Methods: The cytotoxic effects of natural products on NCI-H1975 cells were assessed using a cell viability assay. NK cell-mediated killing was evaluated in a co-culture system. The expression of MICA/B, Fas, and TRAIL receptors (DR4 and DR5) was analyzed by flow cytometry. Results: Treatment with a natural product and NK cells significantly enhanced cancer cell toxicity compared with either treatment alone. Mechanistically, KS markedly increased the expression of TRAIL death receptors on NCI-H1975 cells. Treatment with KS at 62.5 μg/mL increased the proportion of DR4-positive cells from 13.4% to 56.7% and DR5-positive cells from 99.0% to 99.9%. Conclusions: These findings indicate that natural products can increase the susceptibility of cancer cells to NK cell-mediated killing by upregulating TRAIL receptor expression and promoting apoptosis. This sensitizing effect may provide a useful strategy to improve the efficacy of cancer immunotherapy.