Peptide-based strategies for overcoming multidrug-resistance in cancer therapy

Despite ongoing advancements in cancer treatment, the emergence of primary and acquired resistance poses a significant challenge for both traditional chemotherapy and immune checkpoint blockade therapies. The demand for targeted therapeutics for multidrug-resistant cancer is more important than ever. Peptides, as emerging alternatives to current anticancer drugs, offer exquisite versatility in facilitating the design of novel oncology drugs, with the core superiorities of good biocompatibility and a low tendency to induce drug resistance. This review comprehensively introduces the pharmacological mechanisms of peptide-based drugs and strategies for overcoming multidrug resistance (MDR) in cancers, including inducing cell membrane lysis, targeting organelles, activating anticancer immune responses, enhancing drug uptake, targeting ATP-binding cassette (ABC) transporters, and targeting B-cell lymphoma-2 (BCL-2) family proteins. Additionally, the current clinical applications of representative peptides in combating MDR cancers and their potential directions for medicinal chemistry research have been thoroughly discussed. This review offers essential insights into the novel treatment approaches for MDR cancers and highlights the trends and perspectives in this field.