AbstractImmunotherapies have shown benefits across a range of human cancers, but not pancreatic ductal adenocarcinoma (PDAC). Recent evidence suggests that the immunosuppressive tumor microenvironment (TME) constitutes an important roadblock to their efficacy. The landscape of the TME differs substantially across PDAC subtypes, indicating context-specific principles of immunosuppression. In this review, we discuss how PDAC cells, the local TME, and systemic host and environmental factors drive immunosuppression in context. We argue that unraveling the mechanistic drivers of the context-specific modes of immunosuppression will open new possibilities to target PDAC more efficiently by using multimodal (immuno)therapeutic interventions.Significance:Immunosuppression is an almost universal hallmark of pancreatic cancer, although this tumor entity is highly heterogeneous across its different subtypes and phenotypes. Here, we provide evidence that the diverse TME of pancreatic cancer is a central executor of various different context-dependent modes of immunosuppression, and discuss key challenges and novel opportunities to uncover, functionalize, and target the central drivers and functional nodes of immunosuppression for therapeutic exploitation.