Pancreatic cancer is one of the most lethal cancer types worldwide, with barely a quarter of the patients still alive one year after diagnosis and a 5-year overall survival below 10%. This dismal outcome is mainly due to its high resistance to all current therapies. Therefore, innovative and effective treatment options are urgently needed for these patients. The tumor microenvironment is stated as the major confounding factor involved in therapy failure. This tumor microenvironment acts as a dense fibrotic shield around the pancreatic cancer cells and additionally creates an immune suppressive environment. Therefore, combination therapies that target both cancer cells and modulate this immune suppressive tumor microenvironment are the next-generation strategies. Hence, in this project I will first modulate the fibrotic shield by using ormeloxifene. This compound is included in the list for drug repurposing in oncology, underlining the fastest and most cost-effective way towards clinical application. Subsequently, I will reinforce the patient's own immune system to eliminate pancreatic cancer cells by exploiting next-generation inhibitory immune checkpoints. With this rationally designed combination, I aim to provide a solid, scientific rationale to initiate a novel clinical trial for pancreatic cancer patients who are in dire need for new treatments options.