Toosendanin Reprograms Macrophages to Enhance Antitumor Immunity

While immune checkpoint inhibitors have revolutionized the treatment of cancer, tumors with low T-cell infiltration or an immunosuppressive microenvironment, such as glioblastoma (GBM), fail to respond to these therapies. Tumor-associated macrophages, which are abundant in GBM tumors, are known to suppress the antitumor T-cell response and mediate therapeutic resistance, making them an attractive target to improve GBM immunotherapy. To identify compounds that could reverse the immunosuppressive phenotype of these macrophages and sensitize GBM to immunotherapies, Yang and colleagues performed a functional drug screen where macrophages derived from human peripheral blood mononuclear cells were cultured with GBM-derived endothelial cells as well as tumor-conditioned medium and treated with a library of small molecules. The top candidate was identified as toosendanin (TSN), which was able to inhibit the expression of immunosuppressive markers in tumor-educated macrophages without affecting their viability. TSN treatment led to increased T-cell activation, and transcriptomic analysis revealed that TSN-treated macrophages downregulated the expression of genes associated with M2-polarization and immunosuppression and upregulated proinflammatory genes. To investigate the effects of TSN on tumor growth and immune infiltration, tumors were induced in a mouse model of GBM and transplanted into wild-type mice. TSN treatment in this mice repolarized intratumoral macrophages to an M1-like proinflammatory state which enhanced CD8⁺ T cell infiltration and activation as well as reduced levels of exhausted and regulatory T cells. This contributed to subsequent tumor regression and increased survival of TSN-treated mice. Moreover, when TSN was administered in combination with immune checkpoint blockade or chimeric antigen receptor T cells, the effects on tumor suppression were even greater than either treatment alone, with complete responses being achieved in some mice. Mechanistically, TSN was found to bind and inhibit Src kinase family members Hck and Lyn, and suppression of either kinase decreased immunosuppressive gene expression in macrophages. Altogether, this study showed that the small molecule TSN can reprogram immunosuppressive macrophages and synergize with immunotherapies to stimulate the T cell–mediated antitumor response in GBM.

Yang F, Zhang D, Jiang H, Ye J, Zhang L, Bagley SJ, et al. Small-molecule toosendanin reverses macrophage-mediated immunosuppression to overcome glioblastoma resistance to immunotherapy. Sci Transl Med 2023;15:eabq3558.

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