Pancreatic cancer is a highly aggressive malignancy with poor prognosis, as it is often diagnosed at an advanced stage and lacks early detection markers. Current treatments, such as chemotherapy and radiotherapy, offer limited survival benefits. Immunotherapy has shown promise in treating pancreatic cancer, but its effectiveness is hindered by the immunosuppressive tumor microenvironment (TME). This review explores the immunosuppressive TME of pancreatic cancer and highlights various immunotherapeutic approaches, including oncolytic virus therapy, CAR T-cell and NK cell therapy, cytokine-induced killer cells, immune checkpoint inhibitors, and cancer vaccines. It also discusses the role of myeloid cells, the gut microbiome, and emerging technologies like CRISPR/Cas9 in immunotherapy. Challenges in pancreatic cancer immunotherapy include the TME's immunosuppressive nature, low mutational burden, and resistance to immune checkpoint inhibitors. The TME is characterized by extensive desmoplasia, a lack of effector T cells, and an immunophenotype dominated by TH2 cells, which facilitate immune evasion. Immune checkpoint inhibitors, such as PD-1 and PD-L1 blockers, have shown limited efficacy due to the TME's immunosuppressive properties. Research is ongoing to enhance immunotherapy by combining it with chemotherapy, surgery, and other treatments to improve outcomes. The role of immune cells, including T lymphocytes, NK cells, dendritic cells, and macrophages, in the TME is complex, with some cells promoting immune evasion and others supporting anti-tumor responses. Myeloid-derived suppressor cells (MDSCs) and neutrophils also contribute to immunosuppression. Non-immune cells, such as pancreatic cancer stem cells (PCSCs) and mesenchymal stem/stromal cells (MSCs), play critical roles in tumor progression and resistance to therapy. Targeting these cells and the TME is a key focus in developing more effective immunotherapies for pancreatic cancer.Pancreatic cancer is a highly aggressive malignancy with poor prognosis, as it is often diagnosed at an advanced stage and lacks early detection markers. Current treatments, such as chemotherapy and radiotherapy, offer limited survival benefits. Immunotherapy has shown promise in treating pancreatic cancer, but its effectiveness is hindered by the immunosuppressive tumor microenvironment (TME). This review explores the immunosuppressive TME of pancreatic cancer and highlights various immunotherapeutic approaches, including oncolytic virus therapy, CAR T-cell and NK cell therapy, cytokine-induced killer cells, immune checkpoint inhibitors, and cancer vaccines. It also discusses the role of myeloid cells, the gut microbiome, and emerging technologies like CRISPR/Cas9 in immunotherapy. Challenges in pancreatic cancer immunotherapy include the TME's immunosuppressive nature, low mutational burden, and resistance to immune checkpoint inhibitors. The TME is characterized by extensive desmoplasia, a lack of effector T cells, and an immunophenotype dominated by TH2 cells, which facilitate immune evasion. Immune checkpoint inhibitors, such as PD-1 and PD-L1 blockers, have shown limited efficacy due to the TME's immunosuppressive properties. Research is ongoing to enhance immunotherapy by combining it with chemotherapy, surgery, and other treatments to improve outcomes. The role of immune cells, including T lymphocytes, NK cells, dendritic cells, and macrophages, in the TME is complex, with some cells promoting immune evasion and others supporting anti-tumor responses. Myeloid-derived suppressor cells (MDSCs) and neutrophils also contribute to immunosuppression. Non-immune cells, such as pancreatic cancer stem cells (PCSCs) and mesenchymal stem/stromal cells (MSCs), play critical roles in tumor progression and resistance to therapy. Targeting these cells and the TME is a key focus in developing more effective immunotherapies for pancreatic cancer.