Why Cancer Immunotherapy Fails?: Mechanisms of Resistance and Emerging Reversal Strategies

Abstract

Cancer immunotherapy has revolutionized the field of oncology by enabling the immune system to target and destroy cancer cells. Therapies such as immune checkpoint inhibitors, including PD-1/PD-L1 and CTLA-4 blockade, and chimeric antigen receptor T (CAR-T) cells have shown unprecedented clinical efficacy, especially in melanoma, non-small cell lung cancer, and hematologic malignancies. These advances have transformed treatment paradigms, leading to significant improvements in outcomes for some patients. However, a major challenge remains: a substantial proportion of patients exhibit primary resistance or relapse after initial response, limiting the broader success of these therapies. In this review, we highlight cancer-intrinsic, immune microenvironment-related, and host-related mechanisms that underlie immunotherapy resistance, including tumor antigen loss, MHC downregulation, immunosuppressive microenvironments, and host factors such as microbiome composition. We also discuss emerging strategies to overcome resistance, such as combination therapies (e.g., checkpoint inhibitors with targeted agents or chemotherapy), novel immune checkpoint targets (e.g., LAG-3, TIM-3, TIGIT), and personalized immunotherapies including neoantigen vaccines. By breaking down the complex biology of resistance and highlighting innovative approaches under development, this review aims to guide future research and clinical efforts toward more durable and widely applicable immunotherapy responses.