Pancreatic neuroendocrine tumors (PNETs) are rare tumors that are often diagnosed at advanced or metastatic stages, resulting in a poor prognosis. Sunitinib is an approved therapy for treatment of patients with PNETs, but low response rates and resistance have limited its impact, with autophagy and sunitinib sequestration in the lysosome identified as key resistance mechanisms. Here, we show that the combination of sunitinib with the procaspase-3 activator PAC-1 enhances PNET cell death in cell culture and in vivo in a xenograft tumor model. PAC-1 treatment enlarges lysosomes, resulting in partial lysosomal membrane permeabilization and blocking of autophagosome-lysosome fusion. These alterations lead to increased accumulation of autophagic structures, blocking autophagic flux, and a changed distribution of sunitinib from the lysosome to the cytosol. Our data show that PAC-1 modulates sunitinib-induced autophagy and blocks lysosomal trapping, potentiating sunitinib activity and increasing death of cancer cells. As both drugs are well-tolerated in patients, the data suggest evaluation of the PAC-1/sunitinib combination in a clinical trial of patients with PNET.