Targeting drug resistance in colorectal cancer using peptide-based scaffolds: new frontiers in colorectal cancer therapy

A formidable clinical challenge, colorectal cancer (CRC) has faced a considerable limitation arising in the form of drug resistance, which in turn has affected the optimum outcome of standard chemotherapy, target therapy, and immunotherapies. Peptide scaffolds, in recent research, have turned out to be an effective tool in tackling multidrug resistance. This article reviews recent observations on peptide-mediated therapy against CRC drug resistance that comprises peptide-drug conjugates, which have shown effective implications in intensifying specific antitumor effects, cell-penetrating peptides, which have shown considerable potential in intensifying antitumor effects, and pro-apoptotic and oncolytic peptides, which exhibit direct antitumor effects by inducing tumor cell death. The vast potential of peptides in inhibiting DNA repairing, cell cycle arrest, apoptosis, gene expression, and the tumor microenvironment has shown their implications in reversing chemotherapy-resistant cancer cells. Furthermore, the integration of peptides into nanocarrier systems is discussed. Immunotherapeutic peptides that restore anti-tumor immunity by overcoming immune evasion mechanisms and the current therapeutic strategies under clinical evaluation are reviewed. Overall, peptide-based scaffolds show preclinical promise in CRC therapy through the novel Mechanistic Resistance Profiling (MRP) Framework, which classifies peptides by targeted resistance layers (efflux, repair, apoptosis, TME, and immune evasion) to guide combination therapies, and clinical validation remains essential.