The role of disulfidptosis-driven tumor microenvironment remodeling in pancreatic cancer progression.

[BACKGROUND] Pancreatic ductal adenocarcinoma (PDAC) continues to pose a significant clinical challenge due to its high mortality rate and limited treatment efficacy. The role of disulfidptosis, a recently discovered mode of regulatory cell death, in pancreatic cancer progression and tumor immunity remains poorly understood.

[METHODS] We developed and validated a disulfidptosis-related prognostic signature based on 13 pivotal genes. Integrated multi-omics approaches, incorporating bulk and single-cell transcriptomics, spatial transcriptomics, and functional assays, were employed to investigate the association between disulfidptosis and key biological processes.

[RESULTS] The prognostic signature effectively stratified PDAC patients into distinct risk categories with markedly different clinical outcomes and exhibited consistent predictive accuracy across multiple independent cohorts. It informed personalized treatment strategies, revealing differential sensitivity to therapeutic agents including dasatinib and UMI-77. Multi-omics analyses revealed that disulfidptosis is closely associated with redox homeostasis, cytoskeletal organization, and immune evasion. The high-risk subgroup displayed an immunosuppressive tumor microenvironment, characterized by diminished CD8 T cell infiltration and altered immune checkpoint expression. UBASH3B was further identified as a core prognostic biomarker, significantly promoting the proliferation and migration of pancreatic cancer cells, while bioinformatic analysis also suggested its association with tumor immune regulation pathway.

[CONCLUSION] Our study develops a novel prognostic framework for patient stratification based on disulfidptosis-related genes in PDAC. Integrated multi-omics analyses reveal a strong association between disulfidptosis and an immunosuppressive tumor microenvironment, positioning it as a candidate metabolic vulnerability that warrants further functional investigation. These findings offer correlative insights into the involvement of disulfidptosis in immune regulation and suggest that further exploration of this pathway may inform future immunotherapeutic strategies.