Peptide-drug conjugates in tumor therapy: Current advances and future perspectives

As a novel targeted therapeutic approach, peptide-drug conjugates (PDCs) integrate peptides, drug payloads, and linkers to establish an efficient drug delivery system. In addition to retaining the selective advantage inherent in targeted therapy, this modular approach confers a spectrum of therapeutic capabilities, such as enhanced drug targeting, controlled drug release, improved bioavailability, and reduced systemic toxicity and immunogenicity. Moreover, by leveraging their active tumor-targeting capacity and stimulus-responsive drug release properties, PDCs could induce immunogenic cell death and synergistically reprogram the immunosuppressive tumor microenvironment, thereby enabling precise intervention in tumors. This strategy exhibits a favorable efficacy-to-toxicity profile and remarkable potential in immunotherapy, ultimately leading to an improved therapeutic index against tumors. Currently, the PDC Lutathera has been approved by the U.S. FDA for the treatment of cancer, and several other PDCs candidates are currently under investigation in clinical trials. This review provides a systematic summary of the recent research progress in PDCs for cancer treatment over the past five years, focusing on the molecular design strategies based on peptides, linkers, and drugs, as well as recent technological breakthroughs, such as PDCs constructed using nano-strategies, and the applications of PDCs in monotherapy and combination therapy. Additionally, the therapeutic advantages, existing challenges and future clinical applications of PDCs are also discussed. This review tries to offer critical insights into PDCs and provides new perspectives for the future development of antitumor therapies.