Pancreatic ductal adenocarcinoma (PDAC) is characterized by a highly complex and immunosuppressive tumor microenvironment (TME) that contributes to therapeutic resistance. A deeper understanding of the cellular and molecular mechanisms orchestrating this ecosystem is therefore crucial for developing novel intervention strategies. In this context, we are employing a multiparametric approach—integrating high-dimensional flow cytometry and mass cytometry (CyTOF)—to dissect the immune landscape of pancreatic cancer in preclinical mouse models. Particular attention is given to the cytokine IL-17A, which has emerged as a critical modulator of tumor-associated immune networks. Our studies aim to unravel how IL-17A shapes immune cell populations and stromal interactions within the TME, and to explore how its depletion may synergize with immunotherapeutic approaches, including next-generation DNA vaccines. By mapping the spatial and functional heterogeneity of the TME, these analyses provide new perspectives on targeting immunoregulatory pathways to overcome resistance and enhance the efficacy of cancer immunotherapy.