The immune checkpoint molecule PD-1 and its ligand PD-L1 play a pivotal role in tumor immune evasion and progression by thwarting apoptosis induced by the immune system. Despite the significant efficacy of anti-PD-1/PD-L1 therapy against solid tumors, durable responses are observed in only a minority of patients. Many patients fail to experience the full benefits of therapy, with a notable proportion eventually developing acquired resistance. Therefore, establishing robust preclinical models of PD-1 resistance is crucial for unraveling resistance mechanisms and devising novel treatment strategies. Common mechanisms contributing to anti-PD-1/anti-PD-L1 resistance include the absence of suitable tumor antigens, tumor surface MHC molecules inactivation, dysregulated IFN-γ signaling pathways, and the immunosuppressive tumor microenvironment.