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.

Dengue virus (DENV) remains a major global health threat, particularly in tropical and subtropical regions, due to the lack of effective antiviral therapies. In this study, we evaluated a novel combination strategy using melittin, a bee venom-derived antiviral peptide, together with Clinacanthus nutans extract to enhance antiviral efficacy while reducing melittin-associated cytotoxicity against dengue virus serotype 2 (DENV-2). Cytotoxicity was assessed in Vero cells using a cell viability assay, whereas antiviral activity was evaluated by focus-forming unit (FFU) reduction assay, cell-based ELISA, FFU titration assay, and immunofluorescence assay (IFA). Melittin (1.25–2.5 µg/mL) and C. nutans extract (15.625–500 µg/mL) maintained cell viability above 80%, whereas 5 µg/mL melittin markedly reduced cell viability. Notably, co-treatment with C. nutans restored cell viability to above 80%, demonstrating a significant cytoprotective effect. More importantly, the combination treatment exhibited greater antiviral activity than either agent alone, resulting in complete inhibition of viral infection at lower concentrations while simultaneously suppressing intracellular viral protein expression and production of progeny viruses. These findings suggest that C. nutans may enhance the antiviral activity of melittin while reducing its cytotoxicity under the conditions tested. Overall, this study provides preliminary evidence supporting the potential of this natural compound-based combination strategy and warrants further preclinical investigation as a candidate antiviral approach against DENV infection.