Selective ADA2 inhibition for enhancing anti-tumor immune response in glioma: Insights from computational screening of flavonoid compounds

Abstract

Brain tumors, particularly gliomas, remain difficult to treat due to their complex and dynamic microenvironment and high mortality rate. The presence of tumor-associated macrophages (TAMs) is considered one of the primary factors contributing to a poor prognosis in Glioma. Previous reports have linked elevated levels of Adenosine deaminase 2 (ADA2) with immunosuppression, tumor progression, and angiogenesis via MAPK, PDGFβ signaling pathway in the glioma microenvironment. In contrast, Adenosine deaminase 1 (ADA1), another type of adenosine deaminase, plays a pivotal role in purine metabolism, which is essential for lymphocyte survival. Hence, selectively targeting ADA2 while preserving ADA1 activity could offer a viable approach for regulating macrophage polarization and enhancing the anti-tumor immune response. In pursuit of this objective, our study employed a computational approach, unveiling the remarkable attributes of Daidzin, characterized by its exceptional specificity, and binding affinity towards ADA2 while displaying minimal affinity towards ADA1. Furthermore, Define Secondary Structure of Proteins (DSSP) analysis revealed that Daidzin elicits conspicuous conformational alterations within the dimerization domain of the ADA2 receptor, which could have a crucial impact on its activity. However, the ADA1 structure remained unaltered. Our study offers the potential use of Daidzin as a specific therapeutic agent for modulating the tumor microenvironment and revolutionizing glioma management.