Peptide inhibitors of immune checkpoints: Bridging the gap toward next-generation cancer immunotherapy

Immune checkpoint blockade therapy has revolutionized cancer treatment and demonstrated significant clinical efficacy. However, conventional monoclonal antibody therapeutics still face numerous limitations. Peptide inhibitors, with their low molecular weight, ease of synthesis, cost-effectiveness, and minimal immunogenicity, offer a promising alternative by combining the high specificity of antibodies with the favorable tissue penetration of small molecules. As such, they represent a key direction for overcoming existing therapeutic bottlenecks and developing next-generation immunotherapies. Despite facing key challenges in clinical translation, particularly regarding metabolic stability and oral bioavailability, peptide-based inhibitors hold considerable potential to bridge the gap between antibodies and small-molecule drugs, positioning them as an important component of next-generation cancer immunotherapy. Currently, research in this field is increasingly shifting from traditional empirical screening to intelligent precision design, employing strategies such as rational design based on hotspot amino acids, AI-assisted drug discovery, and advanced delivery systems to optimize the activity, stability, and targeting properties of peptides. This review systematically outlines recent advances in immune checkpoint peptide-based inhibitors, aiming to provide a theoretical foundation for the rational design and clinical translation of this emerging class of therapeutics.