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Strategies to Overcome PD-1/PD-L1 Blockade Resistance: Focusing on Combination with Immune Checkpoint Blockades

Dinglin Liu,Haoyue Xiao,Ying Xiang,Dian Zhong,Yuchen Liu,Yunfei Wang,Weijia Zhang

Published 2025 in Journal of Cancer

ABSTRACT

In recent years, immune checkpoint blockades (ICBs) have made rapid progress in the field of cancer treatment, providing significant therapeutic effects and survival benefits, especially in patients with advanced refractory tumors. PD-1/PD-L1 blockade is one of the most widely used ICBs. However, its application is limited by low response rate and drug resistance. It is of great significance to investigate the complex mechanisms of PD-1/PD-L1 blockade resistance. In this review, we outline some crucial aspects, including lack of effector T cells, lack of target PD-1/PD-L1, poor immunogenicity of tumors, immunosuppressive TME, and other mechanisms (such as metabolism, epigenetic alterations, and gut microbiota). Combination therapy has become a promising strategy to overcome drug resistance. Based on the upregulation of other immune checkpoints after PD-1/PD-L1 blockade treatment, we focus on the combination with other ICBs, including CTLA-4, TIM-3, LAG-3, TIGIT, VISTA, and some emerging immune checkpoints, so as to provide evidence for improving the benefit of ICBs in cancers.

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