Pancreatic cancers rely heavily on autophagy for tumor growth. This study shows that pancreatic cancer cells have elevated autophagy under normal conditions, and inhibiting autophagy leads to increased reactive oxygen species (ROS), DNA damage, and metabolic defects, resulting in reduced tumor growth. Genetic or pharmacological inhibition of autophagy, such as using chloroquine, causes significant tumor regression and prolonged survival in mouse models. Unlike other cancers where autophagy inhibition may help with chemotherapy, pancreatic cancers depend on autophagy for their growth, making it a promising therapeutic target. Chloroquine and its derivatives, which are already used safely in humans, could be effective in treating pancreatic cancer and other cancers that rely on autophagy. The study highlights the importance of autophagy in pancreatic cancer progression and suggests that targeting autophagy could be a novel approach for treatment.Pancreatic cancers rely heavily on autophagy for tumor growth. This study shows that pancreatic cancer cells have elevated autophagy under normal conditions, and inhibiting autophagy leads to increased reactive oxygen species (ROS), DNA damage, and metabolic defects, resulting in reduced tumor growth. Genetic or pharmacological inhibition of autophagy, such as using chloroquine, causes significant tumor regression and prolonged survival in mouse models. Unlike other cancers where autophagy inhibition may help with chemotherapy, pancreatic cancers depend on autophagy for their growth, making it a promising therapeutic target. Chloroquine and its derivatives, which are already used safely in humans, could be effective in treating pancreatic cancer and other cancers that rely on autophagy. The study highlights the importance of autophagy in pancreatic cancer progression and suggests that targeting autophagy could be a novel approach for treatment.