Original: https://doi.org/10.1016/j.bioactmat.2025.07.042
Resistance to immunotherapy is still a major challenge in treating lung adenocarcinoma (LUAD). To improve treatment outcomes, it is important to find new and effective targets for immunotherapy. By analyzing public databases, we identified ADPRHL1 (also called ARH2) as a gene linked to immune suppression.
In this study, we showed that LUAD tumors with more ARH2-positive macrophages have stronger immunosuppressive environments. ARH2 pushes macrophages toward the M2 type, which supports tumor growth, and weakens the immune response by affecting the FPR2/PI3K/AKT signaling pathway.
We also discovered that artesunate (ART) can cause a form of programmed cell death called necroptosis in LUAD cells and can help activate the immune system against tumors.
To turn these findings into a treatment strategy, we created a pH- and ROS-responsive nanosystem that delivers both siARH2 (to silence ARH2) and ART. This nanosystem activates immune responses in tumor cells and in tumor-associated macrophages. It also showed good safety in animal studies, accurately targeted PD-L1, and responded well to changes in pH and ROS levels in the tumor environment.
The nanosystem greatly reduced the cancer-promoting behavior of macrophages and strengthened T-cell–based antitumor immunity.
Overall, combining ARH2 targeting with ART treatment offers a promising new therapeutic strategy for LUAD.