A tumor-penetrating peptide, iRGD (CRGDK/RGPD/EC), enhances the efficacy of cancer drugs by increasing vascular and tissue permeability in tumors. This peptide, which binds to αv integrins on tumor blood vessels, is cleaved to produce CRGDK/R, which then binds to neuropilin-1 (NRP-1), enabling tumor-specific tissue penetration. When coadministered with various cancer drugs, including small molecules, nanoparticles, and monoclonal antibodies, iRGD significantly improves drug delivery and therapeutic outcomes. This approach allows the use of already approved drugs without chemical modification, reducing side effects and improving therapeutic index. Studies show that iRGD increases the accumulation of drugs in tumors, enhancing their penetration and effectiveness. For example, when coadministered with doxorubicin (DOX), iRGD increased DOX accumulation in tumors by 7-fold and improved tumor growth inhibition. Similarly, when combined with nab-paclitaxel, iRGD enhanced drug delivery to breast and prostate tumors. The combination also reduced cardiotoxicity associated with DOX, maintaining similar toxicity levels as the drug alone. iRGD also improved the delivery of trastuzumab, a monoclonal antibody used in breast cancer treatment, by increasing its accumulation in tumors by 40-fold. This combination therapy effectively eradicated tumors in mice, even at lower drug doses. The effectiveness of iRGD was observed in various tumor models, including human breast and prostate cancers. The mechanism of iRGD involves receptor-mediated and energy-dependent processes, distinct from the passive leakage seen in the Enhanced Permeability and Retention (EPR) effect. iRGD's ability to enhance drug penetration is effective for both small molecules and nanoparticles, making it a versatile tool for improving cancer therapy. Future improvements could include using multimeric iRGD or other CendR peptides to further enhance drug delivery. The results suggest that iRGD-based combination therapy could improve the efficacy of a wide range of cancer drugs while reducing toxicity, aligning with the goals of modern cancer treatment.A tumor-penetrating peptide, iRGD (CRGDK/RGPD/EC), enhances the efficacy of cancer drugs by increasing vascular and tissue permeability in tumors. This peptide, which binds to αv integrins on tumor blood vessels, is cleaved to produce CRGDK/R, which then binds to neuropilin-1 (NRP-1), enabling tumor-specific tissue penetration. When coadministered with various cancer drugs, including small molecules, nanoparticles, and monoclonal antibodies, iRGD significantly improves drug delivery and therapeutic outcomes. This approach allows the use of already approved drugs without chemical modification, reducing side effects and improving therapeutic index. Studies show that iRGD increases the accumulation of drugs in tumors, enhancing their penetration and effectiveness. For example, when coadministered with doxorubicin (DOX), iRGD increased DOX accumulation in tumors by 7-fold and improved tumor growth inhibition. Similarly, when combined with nab-paclitaxel, iRGD enhanced drug delivery to breast and prostate tumors. The combination also reduced cardiotoxicity associated with DOX, maintaining similar toxicity levels as the drug alone. iRGD also improved the delivery of trastuzumab, a monoclonal antibody used in breast cancer treatment, by increasing its accumulation in tumors by 40-fold. This combination therapy effectively eradicated tumors in mice, even at lower drug doses. The effectiveness of iRGD was observed in various tumor models, including human breast and prostate cancers. The mechanism of iRGD involves receptor-mediated and energy-dependent processes, distinct from the passive leakage seen in the Enhanced Permeability and Retention (EPR) effect. iRGD's ability to enhance drug penetration is effective for both small molecules and nanoparticles, making it a versatile tool for improving cancer therapy. Future improvements could include using multimeric iRGD or other CendR peptides to further enhance drug delivery. The results suggest that iRGD-based combination therapy could improve the efficacy of a wide range of cancer drugs while reducing toxicity, aligning with the goals of modern cancer treatment.