ACT001 conquers Temozolomide-Chemoradiotherapy Resistance in Refractory Glioblastoma via the TNF-CXCL10-CD8+ T Cell Axis to Achieve Immune-Mediated Cure
Glioblastoma multiforme (GBM), as a highly invasive brain tumor, is severely restricted in T-cell infiltration and anti-tumor activity due to its immunosuppressive microenvironment. This study reveals the mechanism by which the small molecule compound ACT001 effectively reshapes the GBM immune microenvironment by specifically upregulating the tumor necrosis factor (TNF) signaling pathway. Experiments show that ACT001 combined with RT/TMZ treatment significantly activates the TNF pathway, inducing tumor cells and stromal cells in the microenvironment to express chemokines CXCL10, thereby promoting the infiltration of T cells, especially CD8+ T cells, to the tumor site. Using the rapid G422TN-GBM growth model, RT/TMZ/ACT001 treatment significantly inhibits tumor growth and prolongs survival, and this effect depends on the increase in T-cell infiltration and can be blocked by TNF pathway inhibitors. These results indicate that ACT001 overcomes the immunosuppressive barrier of GBM by targeting the activation of the TNF signaling pathway, enhancing T-cell-dependent anti-tumor immunity, forming the TNF-CXCL10-CD8+ T cell axis, and providing a new strategy for the immunotherapy of GBM.