Importantly, we show that the observed LAPTM5-mediated tumor-suppressive and temozolomide-sensitizing effects are exclusively observed in CD40-expressing glioblastoma cells, indicating an intact CD40–LAPTM5 axis as a prerequisite for the tumor-suppressive activity of LAPTM5. Silencing of CD40 in CD40-positive U87MG cells abolished the pro-tumorigenic and temozolomide-resistant properties of LAPTM5 knockdown cells, whereas CD40 overexpression in primarily CD40-negative glioblastoma cells recreated the aggressive phenotype and temozolomide resistance of LAPTM5 knockdown cells. Here, CD40 is linked to glioblastoma.