The role of ferroptosis regulators in the prognosis, immune activity and gemcitabine resistance of pancreatic cancer

Background: Ferroptosis is a novel form of regulated cell death that can inhibit the progression of chemotherapy-resistant tumors. However, the types of cancer most susceptible to ferroptosis induction and the role of ferroptosis regulators in cancers, especially pancreatic cancer, remain unclear.

Methods: RNA sequencing data of 31 cancers were collected from The Cancer Genome Atlas (TCGA) and The Genotype-Tissue Expression (GTEx). A nomogram integrating patients' clinical information and risk scores based on the expression levels of ferroptosis regulators was depicted. Correlations among the activity levels of 29 immunity-associated gene sets, immune scores, infiltrating immune cells and key ferroptosis regulators were assessed.

Results: We performed a pan-cancer analysis and identified 14 distinct cancers that may show a robust response to ferroptosis inducers. Interestingly, the Xc-complex, which is the major target of ferroptosis induction, was upregulated in gemcitabine-resistant pancreatic cancer cells (P<0.05). Furthermore, we focused on the role of ferroptosis regulators in mediating the survival of patients with pancreatic cancer and constructed a prognostic model with good accuracy (AUC =0.713). We also correlated elevated sensitivity to ferroptosis with higher scores for CD8+ T cells (P<0.001), the type two interferon response (P<0.001) and immune checkpoints (P<0.05).

Conclusions: We hypothesized that the ferroptosis pathway plays an important role in the prognosis of pancreatic cancer. Immuno- and chemotherapy combined with a ferroptosis inducer is a feasible therapeutic approach for pancreatic cancer.