Abstract: Gastric cancer (GC) is one of the most prevalent malignant tumors worldwide. Although the incidence of GC has significantly decreased over the past decade owing to advancements in early stage diagnostic techniques, its mortality rate remains high. Immune checkpoint inhibitors (ICIs), such as programmed cell death protein-1 (PD-1) inhibitors, have become a promising treatment option for patients with GC. However, only a minority of patients with GC exhibit durable responses to PD-1 inhibitor therapy. Moreover, the overall efficacy of these treatments is limited. Existing studies have indicated that immunotherapeutic failure is closely associated with the development of resistance to PD-1 inhibitors; however, the mechanisms underlying this resistance are not fully understood. Therefore, this review aimed to explore the potential molecular mechanisms contributing to the resistance to PD-1 inhibitors in the treatment of GC and provide a new research perspective on the clinical responses to this resistance.