Ophiopogonin D suppresses non-small cell lung cancer progression by targeting exosomal MALAT1 to enhance dendritic cell maturation

Tumor-immune cell crosstalk critically shapes the progression of non-small cell lung cancer (NSCLC), yet the mechanisms underlying exosome-mediated immune suppression remain incompletely understood. Here, we identify a previously unrecognized exosomal lncRNA-mediated immunoregulatory axis targeted by the natural compound Ophiopogonin D (OP-D). Transcriptomic profiling and mechanistic rescue experiments revealed that Lewis lung carcinoma (LLC)-derived exosomal MALAT1 suppresses dendritic cell (DC) maturation by increasing SIRT1 expression and attenuating p65 phosphorylation. Computational modeling combined with molecular dynamics simulation predicted a stable interaction between OP-D and MALAT1, which was further validated by biolayer interferometry (BLI) and microscale thermophoresis (MST) assays, supporting MALAT1 as a direct molecular target of OP-D. In vivo, OP-D markedly inhibited tumor growth and enhanced intratumoral DC activation. Mechanistically, OP-D reduced MALAT1 abundance in LLC-derived exosomes and decreased the accumulation of exosomal MALAT1 in recipient DCs, thereby suppressing SIRT1 signaling, restoring p65 phosphorylation, and promoting DC maturation and antitumor immune responses. Furthermore, MALAT1 overexpression attenuated the immunostimulatory effects of OP-D, confirming the functional importance of the exosomal MALAT1-SIRT1/p-p65 axis. Collectively, these findings identify exosomal MALAT1 as a critical mediator of tumor-induced DC dysfunction and establish OP-D as a promising immunomodulatory natural compound capable of reprogramming tumor-immune communication in NSCLC.