Background: Neoadjuvant immune checkpoint inhibitors (ICIs) have shown certain effectiveness in resectable gastric cancer (GC), but the efficacy of conversion ICIs in initially unresectable locally advanced or oligometastatic GC is unclear, particularly regarding efficacy prediction and drug resistance mechanisms through multi-omics analysis. Methods: This is a single-arm, retrospective real-world study to evaluate the efficacy of ICI-containing neoadjuvant/conversion treatment for patients with unresectable locally advanced or oligometastatic GC. Primary endpoints included complete pathological response (pCR) rate, major pathological response (MPR) rate, and R0 resection rate. Secondary endpoints were overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), and safety. Exploratory endpoint was the correlation between tumor genetic characteristics and treatment efficacy. Results: Of the 73 included patients, including 64.4% stage cIVa and 10.9% cIVb, 60 (82.2%) underwent radical surgery after conversion combination treatment. The pCR and MPR rates were 28.6% (95% CI 17.1–40.0%), 42.9% (95% CI 30.3–55.4%), with median DFS/PFS at 30.9 (95% CI 16.0-NA) and mOS at 41.3 (95% CI 23.9-NA) months. The stage IV patients achieved 76.4% R0 resection rate, 24.4% pCR rate, and 40.0% MPR rate, with significantly longer OS for R0 patients versus non-R0 ones (HR: 0.22, 95% CI 0.07-0.70, P = 0.0002), and 1-year OS rate 95.2% vs. 64.2%, the 2-year OS rates 71.1% vs. 9.2%, respectively. Even the mOS of stage IV nonMPR patients are significantly prolonged than that of nonR0 ones, indicating that the implementation of R0 surgery was more crucial than MPR. For stage IV patients of R0-MPR, R0-nonMPR and nonR0, the the 3-year OS rates were 85.0%, 51.3%, and near 0, respectively. Subgroup analysis identified significant correlations between pathological responses and pathological type, PD-L1 expression, and tumor mutational burden. The toxicity and post-surgery complications were manageable. Multi-omics analysis revealed that KMT2D mutations were associated with improved clinical outcomes and enhanced immune responses, while tumor cytochrome P450 was linked to treatment resistance. Additionally, an efficacy-predictive model PEMIT was established using an 8-gene panel and was confirmed to surpass common biomarkers such as PD-L1, tumor mutational burden, and mismatch repair status. Conclusions: ICIs-based neoadjuvant/conversion therapy demonstrated promising survival benefits and acceptable safety profiles for patients with unresectable locally advanced and oligometastatic GC, providing a valuable treatment option for this population. Multi-omics findings uncovered mechanisms of drug resistance and provided potential efficacy-related biomarkers.