Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal gastrointestinal malignancies, characterized by dense desmoplastic stroma, hypoxia-driven metabolic reprogramming, and a profoundly immunosuppressive tumor microenvironment, all of which restrict the efficacy of immune checkpoint inhibitors. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a potential strategy to enhance tumor immunogenicity and sensitize PDAC to immunotherapy. However, ferroptosis exerts context-dependent effects in tumor immunity. While ferroptosis induction in PDAC cells may promote antigen release and antitumor immune activation, excessive lipid peroxidation may also impair CD8⁺ T cells and natural killer cells, thereby aggravating immune dysfunction. This review proposes a framework of cell-selective ferroptosis threshold regulation to clarify the balance between tumor-cell ferroptosis induction and effector immune-cell protection in PDAC immunotherapy.

We systematically summarize recent basic and translational studies on PDAC, ferroptosis, immunotherapy, lipid metabolism, the tumor microenvironment, and immune-cell functional regulation. Particular attention was given to studies involving cellular models, pancreatic cancer organoids, KPC mouse models, multi-omics analyses, and combinatorial immunotherapeutic strategies. Focusing on key ferroptosis-regulatory axes, including SLC7A11-GSH-GPX4, FSP1-CoQ10, ACSL4-mediated polyunsaturated fatty acid phospholipid remodeling, iron metabolic dysregulation, mitochondrial oxidative stress, and the NRF2 antioxidant pathway, we constructed a regulatory network of ferroptosis susceptibility in PDAC cells. In parallel, we analyzed the bidirectional crosstalk between ferroptosis and the immunosuppressive microenvironment from the perspectives of CD8⁺ T cells, natural killer cells, tumor-associated macrophages, myeloid-derived suppressor cells, and cancer-associated fibroblasts.

Current evidence indicates that PDAC cells are exposed to persistent oxidative and metabolic stress but acquire ferroptosis resistance through upregulation of SLC7A11, enhanced cysteine uptake, maintenance of GSH-GPX4-dependent antioxidant defense, activation of NRF2 signaling, and stromal metabolic support. Cancer-associated fibroblasts may further increase ferroptosis tolerance by reprogramming cysteine metabolism. Conversely, immunotherapy-activated CD8⁺ T cells can secrete interferon-γ, suppress SLC3A2/SLC7A11 expression through JAK-STAT-related signaling, reduce cystine uptake, and promote lipid peroxidation-mediated ferroptosis in tumor cells. This suggests a potential positive feedback loop linking immune activation, ferroptosis induction, antigen release, and subsequent immune reactivation.

Nevertheless, persistent lipid peroxidation may produce opposite effects. For example, CD36-mediated fatty acid uptake can induce lipid peroxidation and ferroptosis-like dysfunction in tumor-infiltrating CD8⁺ T cells, reducing cytotoxic effector molecule production and weakening antitumor immunity. In addition, ferroptosis-associated lipid peroxidation products, necrosis-like cellular debris, and iron metabolic dysregulation may promote macrophage polarization, myeloid-derived suppressor cell accumulation, and immunosuppressive mediator release.

Ferroptosis-based immunotherapy for PDAC should not aim simply to maximize ferroptosis induction. Instead, a cell-selective strategy is needed: lowering the ferroptosis threshold in tumor cells while preserving lipid peroxidation homeostasis in effector immune cells. This framework may provide a mechanistic basis for overcoming PDAC immunotherapy resistance and guide rational combinations of ferroptosis inducers, immune checkpoint inhibitors, stromal metabolic interventions, and T-cell protective strategies.