Andrographolide suppresses non-small-cell lung cancer progression through induction of autophagy and antitumor immune...

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Non-small-cell lung cancer (NSCLC) treatment outcomes remain poor despite advancements.
• Andrographolide (AD), derived from Andrographis paniculata, possesses known anti-cancer properties.
• The specific mechanisms of AD in NSCLC were previously uncharacterized.

Purpose of the Study:

• To investigate the pharmacological mechanisms of Andrographolide (AD) in non-small-cell lung cancer (NSCLC).
• To explore AD's effects on autophagy, PD-L1 expression, and immune response in NSCLC.
• To evaluate AD's potential as a therapeutic agent and in combination with immunotherapy for NSCLC.

Main Methods:

• Molecular dynamics simulations to assess AD's binding affinity to STAT3.
• Proteomics analysis to determine AD's impact on JAK2/STAT3 signaling and PD-L1 expression.
• In vivo studies using NSCLC xenograft and Lewis lung carcinoma models in mice.

Main Results:

• AD directly binds to STAT3, inhibiting its phosphorylation and suppressing tumor PD-L1 expression via the JAK2/STAT3 pathway.
• AD modulates P62-dependent selective autophagic degradation of PD-L1.
• AD demonstrated tumor growth suppression, prolonged survival in mice, and enhanced anti-PD-1 immunotherapy efficacy by boosting CD8+ T cell activity.

Conclusions:

• Andrographolide (AD) inhibits NSCLC progression through STAT3 signaling and PD-L1 regulation.
• AD enhances the efficacy of anti-PD-1 mAb immunotherapy by promoting CD8+ T cell responses.
• Combination therapy with AD and anti-PD-1 mAb immunotherapy presents a promising strategy for NSCLC treatment.