T cell–based immunotherapy holds promise for treating solid tumors, but its therapeutic efficacy is limited by intratumoral immune suppression. This immune suppressive tumor microenvironment is largely driven by tumor-associated myeloid cells, including macrophages. Here, we report that toosendanin (TSN), a small-molecule compound, reprograms macrophages to enforce antitumor immunity in glioblastoma (GBM) in mouse models. Our functional screen of genetically probed macrophages with a chemical library identifies that TSN reverses macrophage-mediated tumor immunosuppression, leading to enhanced T cell infiltration, activation, and reduced exhaustion. Chemoproteomic and structural analyses revealed that TSN interacts with Hck and Lyn to abrogate suppressive macrophage immunity. In addition, a combination of immune checkpoint blockade and TSN therapy induced regression of syngeneic GBM tumors in mice. Furthermore, TSN treatment sensitized GBM to Egfrviii chimeric antigen receptor (CAR) T cell therapy. These findings suggest that TSN may serve as a therapeutic compound that blocks tumor immunosuppression and circumvents tumor resistance to T cell–based immunotherapy in GBM and other solid tumors that warrants further investigation.
Toosendanin reprograms macrophage immunity and sensitizes glioblastoma to T cell–based immunotherapy.
Glioblastoma (GBM) is a common aggressive brain tumor that is known to have an immunosuppressive tumor microenvironment (TME) and thus is resistant to immunotherapy. To overcome this, Yang et al . have identified that the small-molecule compound toosendanin (TSN) is able to reprogram macrophages to create an antitumor TME in GBM mouse models. The authors performed chemoproteomic and structural analyses to identify that TSN interacts with Hck and Lyn to reduce suppressive macrophages. In addition, they demonstrated increased survival of mice treated with TSN in combination with other immunotherapies, which warrants further investigation for the treatment of GBM and other solid tumors. —DH