An integrated SII-PNI immune-nutritional scoring system predicts efficacy and immune-related adverse events in locally advanced gastric cancer patients undergoing neoadjuvant immunotherapy

Background: Immune checkpoint inhibitors (ICIs) have transformed treatment of locally advanced gastric cancer (LAGC), yet response heterogeneity and immune-related adverse events (irAEs) remain major challenges. Systemic inflammation and nutritional status critically modulate antitumor immunity. This study evaluated the dual predictive value of a combined Systemic Immune-Inflammation Index and Prognostic Nutritional Index (SII-PNI) score for therapeutic efficacy and safety in LAGC patients receiving neoadjuvant PD-1/PD-L1 inhibitor-based therapy. Methods: We retrospectively analyzed 276 LAGC patients who received PD-1/PD-L1 inhibitor-based neoadjuvant immunotherapy (January 2019-December 2021). Blood samples were collected within 7 days before treatment initiation. Optimal cut-off values for SII and PNI were determined via ROC analysis to construct the SII-PNI score (Score 0-2). Primary endpoints were disease-free survival (DFS), overall survival (OS), tumor response (RECIST 1.1), and irAE incidence. Results: The optimal cut-off values were 736.2 for SII and 48.5 for PNI. Patients with a high SII-PNI score (Score 2) exhibited significantly poorer objective response rates (ORR) compared to the low-risk Score 0 group (22.6% vs. 71.2%, P < 0.001). The SII-PNI score demonstrated superior predictive accuracy for immunotherapy response (AUC = 0.750) compared to PD-L1 CPS (AUC = 0.711) and Tumor Mutational Burden (TMB, AUC = 0.625). Multivariate Cox analysis identified the SII-PNI score as an independent prognostic factor; compared to Score 0, patients with Score 2 faced a more than threefold increased risk of disease recurrence (HR = 3.45, 95% CI: 2.40-4.95, P < 0.001) and mortality (HR = 3.15, 95% CI: 1.85-5.36, P < 0.001). Furthermore, the high-risk group (Score 2) had a significantly higher incidence of severe (Grade 3-4) irAEs compared to the low-risk group (28.6% vs. 3.6%, P < 0.001). Conclusions: The SII-PNI score is a robust, non-invasive, and economically accessible biomarker that effectively stratifies outcomes in gastric cancer patients receiving neoadjuvant immunotherapy. It serves as a dual predictor for both poor therapeutic response and increased toxicity, outperforming traditional biomarkers like PD-L1 CPS. This scoring system holds promise for guiding personalized treatment strategies and optimizing patient selection.