The interplay between tumor-intrinsic KRT6A and host-derived immune-nutritional status (PNI) defines prognosis in resectable PDAC

Current anatomic staging inadequately predicts outcomes in resectable pancreatic ductal adenocarcinoma (PDAC). This study integrates tumor-intrinsic KRT6A expression with host-derived prognostic nutritional index (PNI) to develop a novel prognostic model. This retrospective study enrolled 105 patients who underwent pancreaticoduodenectomy for histologically confirmed PDAC between January 2019 and December 2024. KRT6A expression was quantified by immunohistochemistry using computer-assisted image analysis. PNI was calculated as serum albumin (g/L) + 5 × lymphocyte count (10⁹/L). The primary endpoint was disease-free survival (DFS). Univariate and multivariate Cox regression analyses were performed to identify independent prognostic factors. A prognostic nomogram (KSI-Nomo) integrating KRT6A and PNI was constructed and validated using time-dependent ROC curves, calibration plots, and decision curve analysis. Risk stratification was performed based on nomogram total points. KRT6A expression was significantly elevated in poorly differentiated tumors and functionally promoted PDAC cell migration and invasion in vitro. Multivariate analysis identified KRT6A expression (HR = 6.337, 95% CI: 1.733-9.540, P = 0.034) and PNI (HR = 0.953, 95% CI: 0.245-1.702, P = 0.014) as the sole independent prognostic factors for DFS, outperforming conventional inflammatory indices (NLR, PLR, SII) and TNM staging. The KRT6A-PNI nomogram demonstrated excellent discriminative accuracy with AUC values of 0.838 (1-year), 0.836 (2-year), and 0.969 (3-year). Calibration curves showed good agreement between predicted and observed survival probabilities. Decision curve analysis confirmed superior net clinical benefit compared to treat-all or treat-none strategies. Risk stratification identified three distinct prognostic groups: low-risk (30% of patients, 3-year DFS rate 52.3%), intermediate-risk (40%, 38.6%), and high-risk (30%, 12.4%) (log-rank P < 0.001). The KRT6A-PNI model provides superior risk stratification for resectable PDAC, enabling personalized treatment decisions.