Synergistic restoration of NK cell cytotoxicity against solid tumors via sLTA-mediated dual-action modulation

Natural killer (NK) cell-based immunotherapy has shown limited efficacy against solid tumors due to impaired NK cell activation and intrinsic tumor resistance. This study investigated whether lipoteichoic acid isolated from Latilactobacillus sakei K101 (sLTA) could overcome NK resistance in HT-29 colon cancer cells.

Using an NK3.3/HT-29 co-culture system, we found that IL-2-activated NK cells alone were insufficient to induce robust cytotoxicity, whereas sLTA restored NK-mediated tumor cell killing. sLTA upregulated NK activating receptors, including NKG2D and natural cytotoxicity receptors, while enhancing MICB expression and suppressing Bcl-2 and other anti-apoptotic genes in HT-29 cells. siRNA-mediated knockdown and Western blot analysis confirmed the involvement of Caspase-3-dependent apoptosis. Transwell and neutralization assays further demonstrated that sLTA-primed HT-29 cells were sensitized to contact-independent cytotoxicity mediated by NK-derived TNF-α and IFN-γ.

sLTA functions as a dual-action immune sensitizer by enhancing NK effector activation and lowering the apoptotic threshold of resistant tumor cells. These findings suggest that sLTA may serve as an adjunct strategy to improve NK cell-based immunotherapy against solid tumors.