Unraveling the mechanism of alkaloids from Sophora alopecuroides Linn combined with immune checkpoint blockade in the treatment of non-small cell lung cancer based on systems pharmacology

Quinolizidine alkaloids, as essential active ingredients extracted from Sophora alopecuroides Linn (SAL), have been proven to be pharmacologically active in a variety of cancers including non-small cell lung cancer (NSCLC). However, whether these alkaloids have substantial benefits in combination with immune checkpoint blockade (ICB) for the treatment of NSCLC is unknown. Here, we explore the potential of these alkaloids in combination with ICB therapy based on a systems pharmacology and bioinformatics approach. We found that 37 alkaloids in SAL have highly similar characteristics in the molecular skeleton, pharmacological properties, and targets. The expression of targets of these alkaloids are significantly correlated with the infiltration level of tumor infiltrating lymphocytes and the expression levels of multiple immune checkpoints in NSCLC. They share similar molecular mechanisms in antitumor immunity. Sophocarpine (Sop) is one of the most representative constituents of these alkaloids. We demonstrated that the Sop promotes PD-L1 expression to improve the effects of PD-L1 blockade treatment via the ADORA1-ATF3 axis. In conclusion, our study identified these alkaloids as promising candidates for the treatment of NSCLC, either alone or in combination with ICB, with potential value for drug development and may provide a promising strategy for improving the survival of NSCLC patients.