Background: Assessment of systemic and local immune responses is crucial in determining the efficacy of cancer interventions. The identification of specific factors that correlate with pathological complete response (pCR) is essential for optimizing treatment decisions. Methods: In this retrospective study, a total of 521 patients diagnosed with gastric adenocarcinoma who underwent curative gastrectomy following preoperative treatment were reviewed. Of these patients, 463 did not achieve pCR (non-pCR) and 58 achieved pCR. Clinicopathological factors were evaluated to identify predictors for pCR using a logistic regression model. Additionally, a smaller cohort (n=76) was derived using propensity score matching to investigate local immune response, specifically the features of tertiary lymphoid structure (TLS) using H&E staining, immunohistochemistry, and multiplex immunofluorescence. Results: The multivariate regression analysis demonstrated a significant association between low systemic inflammatory status and pCR, as evidenced by reduced levels of the combined systemic immune-inflammation index (SII) and neutrophil-to-lymphocyte ratio (NLR) (SII+NLR) (odds ratio: 3.33, 95% CI: 1.79–6.17, P<0.001). In the smaller cohort analysis, distinct TLS characteristics were correlated with the presence of pCR. Specifically, a higher density of TLS and a lower proportion of PD1+ cells and CD8+ cells within TLS in the tumor bed were strongly associated with pCR. Conclusion: Both systemic and local immune profile were associated with pCR. A low level of SII+NLR served as an independent predictor of pCR, while distinct TLS features were associated with the presence of pCR. Focusing on the immune profile was crucial for optimal management of gastric cancer patients receiving preoperative treatment.