Pterostilbene Inhibits Non-Small Cell Lung Cancer Progression by Activating the STING Pathway and Enhancing Antitumor Immune Response

Liping Kangpan XuCong XuDonghui Huangzebo Jiang^*

• Affiliated Zhuhai Hospital, Southern Medical University, Zhuhai Hospital of Integrated Traditional Chinese & Western Medicine, Zhuhai 519000, Guangdong, China., Zhuhai, China

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. Current therapeutic regimens often yield limited efficacy and fail to achieve durable remissions. In this study, we investigated the antitumor potential and mechanisms of pterostilbene (PTE), a natural stilbenoid with superior bioavailability compared to resveratrol. In vitro assays using A549 and H358 NSCLC cell lines demonstrated that PTE treatment concentration-dependently and time-dependently suppressed cell viability, with half-maximal inhibitory concentrations (IC₅₀) of 7.46 μM and 29.3 μM, respectively, after 48 hours of exposure. PTE induced G2/M phase cell cycle arrest and mitochondrial-dependent apoptosis, primarily driven by intracellular reactive oxygen species (ROS) elevation, as pretreatment with N-acetylcysteine (NAC) abolished these effects. At the molecular level, PTE triggered DNA damage and robustly activated the STING-dependent signaling cascade, leading to phosphorylation of TBK1 and IRF3 and subsequent secretion of T-cell chemoattractants, including CXCL10, CXCL9, and CCL5. Critically, both siRNA-mediated STING knockdown and pharmacological inhibition with H-151 markedly attenuated PTE-induced cytotoxicity and chemokine expression In vivo, PTE treatment significantly suppressed tumor growth in H358 xenograft and immunocompetent LLC1 murine models. Flow cytometric immunoprofiling of LLC1 tumors revealed a substantial increase in granzyme B⁺, TNF-α⁺, and IFN-γ⁺ tumor-infiltrating CD8⁺ T lymphocytes, concomitant with a reduction in myeloid-derived suppressor cells and regulatory T cells. Collectively, our findings elucidate a dual mechanism through which PTE directly eliminates NSCLC cells via ROS-mediated apoptosis and concurrently reinvigorates antitumor immunity through STING pathway activation, positioning it as a promising candidate for combination immunotherapy in NSCLC.