Pancreatic ductal adenocarcinoma (PDAC) is characterised by two major hallmarks. First, insufficient therapeutic treatment options leading to poor prognosis and short survival rates and second, a complex stromal reaction quantitatively exceeding the one found in other tumours. To date, the conflictive interaction of malignant cells with the tumour microenvironment are insufficiently understood and functional model systems are lacking. We investigated the role and interaction of infiltrating lymphocytes as well as myeloid-derived cells in the context of PDAC using genetically engineered mouse (GEM) models which particularly recapitulate human tumourigenesis and desmoplasia. Employing a novel combined Cre/Lox-Flp/Frt approach we were able to activate or abolish canonical Notch-signalling genetically in a myeloid-restricted manner in addition to pancreas-restricted Kras-driven tumourigenesis. While lymphocytes did not influence tumour development markedly, myeloid Notch-activation was found not only to diminish M2-macrophage polarisation but also to perturb recruitment of immature myeloid cells in vivo . By opening an avenue to overcome the immunosuppressive state fostered Notch-signalling in myeloid cells revealed prolonged survival of GEMs. Here we describe a genetic animal model functionally reprogramming tumour-associated myeloid cells. To our knowledge, this provides the first functional proof of the macrophage polarisation concept in an endogenous mouse tumour model.