Prognostic and Immunological Significance of TIPARP in Pancreatic Cancer.

BACKGROUND

Pancreatic ductal adenocarcinoma (PAAD) remains one of the most lethal malignancies, with a 5-year survival rate below 10%. TCDD-inducible poly (ADP-ribose) polymerase (TIPARP) is aberrantly expressed in various tumors, but its mechanistic role and clinical significance in pancreatic cancer remain unclear.

METHODS

We analyzed TIPARP expression patterns and prognostic relevance by integrating data from the TCGA-PAAD (n = 178) and GTEx (n = 171) databases. Single-cell RNA sequencing, immune infiltration profiling, and Mendelian randomization analyses were conducted to assess cell-type specificity and causal relationships. The biological functions of TIPARP were validated through in vitro assays, and downstream mechanisms were explored via pathway enrichment analysis.

RESULTS

TIPARP was significantly upregulated in pancreatic cancer tissues and correlated with worse overall survival (P = 5.9e - 3) and progression-free survival (P = 0.01), serving as an independent prognostic risk factor. A TIPARP-based nomogram exhibited strong predictive performance (C-index = 0.666; 5-year AUC = 0.885). Single-cell transcriptomics identified fibroblasts as the primary TIPARP-expressing cell type. Immune profiling revealed that high TIPARP expression was associated with altered immune cell infiltration and positively correlated with immune checkpoint molecules such as PD-L1 and TIM-3. Mendelian randomization confirmed a causal association between genetically predicted TIPARP expression and increased PAAD risk (OR = 1.511, P = 0.008). Functional assays showed that TIPARP promotes cell proliferation, migration, and invasion, while pathway analysis implicated the PI3K-Akt and ECM-receptor interaction signaling cascades.

CONCLUSION

TIPARP is a novel independent prognostic biomarker and potential therapeutic target in pancreatic cancer. It contributes to tumor progression by promoting an immunosuppressive microenvironment and activating pro-tumorigenic signaling. These findings highlight TIPARP as a promising candidate for precision medicine and combination immunotherapy in PAAD.