Improvement of the Anticancer Efficacy of PD‐1/PD‐L1 Blockade: Advances in Molecular Mechanisms and Therapeutic Strategies

ABSTRACT The clinical success of PD‐1/PD‐L1 blockade has revolutionized cancer immunotherapy. However, the issues of immune resistance have become increasingly prominent, representing a critical limitation in modern oncology. This phenomenon has prompted efforts to elucidate the mechanisms underlying both types of resistance and to find breakthrough therapeutic strategies. This article provides a comprehensive overview of PD‐1/PD‐L1 blockade resistance mechanisms from both primary and acquired resistance perspectives, including tumor intrinsic factors, immune microenvironment components, and systemic factors. Building on this foundation, emerging research demonstrates that type I interferons (IFNs), particularly IFN‐α and IFN‐β, play crucial immunomodulatory roles in overcoming resistance to PD‐1/PD‐L1 blockade. We delineate six molecular mechanisms through which IFN‐α/β enhance PD‐1/PD‐L1 blockade efficacy, and innovative strategies are proposed to therapeutically boost IFN‐α/β production, including gene editing techniques, targeting the cGAS‐STING or TLR pathway and so on. Furthermore, insights into current challenges and future directions of the application of IFN‐α/β to improve PD‐1/PD‐L1 blockade are discussed. This review holds significant academic value by not only synthesizing current knowledge on PD‐1/PD‐L1 resistance mechanisms but also pioneering a framework for leveraging type I IFNs to overcome these barriers.