Glioblastoma is an aggressive primary brain cancer with poor prognosis and limited therapeutic options. In tumors, glioblastoma cells control their microenvironment through the secretion of proteins and other factors. Work from our lab has identified a new unconventional secretion mechanism that is dependent on VAMP7, a tetanus neurotoxin insensitive v-SNARE. We have shown that Endoplasmic Reticulum (ER) and mitochondrial fragments can be incorporated into late endosomes and can later be released by an unconventional secretory mechanism. This process is more efficient in the absence of degradative autophagy. The v-SNARE VAMP7 has also recently been linked to the progression of various cancers. Here, we highlight the direct link between ER homeostasis and VAMP7-dependent autophagic secretion and that human glioblastoma expressing low levels of VAMP7 are more aggressive than those with higher levels of VAMP7 expression, thus resulting in reduced patient survival. Using combination syngeneic orthografts in a rat model, proteomics and transcriptomics approaches, we document the mechanisms by which VAMP7-dependent secretion impacts on glioblastoma cell survival and tumor progression.