The study investigates the enhancement of cancer drug efficacy by co-administering a tumor-penetrating peptide, iRGD (CRGDK/RGPD/EC), which increases vascular and tissue permeability in a tumor-specific and neuropilin-1-dependent manner. This effect does not require chemical conjugation of the drugs to the peptide. Systemic injection of iRGD improved the therapeutic index of various drugs, including small molecules (doxorubicin), nanoparticles (nab-paclitaxel and doxorubicin liposomes), and monoclonal antibodies (trastuzumab). The combination therapy provided equivalent or better anti-tumor efficacy at a lower dose of the drug, reducing toxicity. The iRGD-mediated enhancement in drug penetration was observed in multiple tumor models and with different drug sizes and chemical properties. The study suggests that co-administering iRGD may be a valuable approach to enhance the efficacy of anti-cancer drugs while reducing side effects.The study investigates the enhancement of cancer drug efficacy by co-administering a tumor-penetrating peptide, iRGD (CRGDK/RGPD/EC), which increases vascular and tissue permeability in a tumor-specific and neuropilin-1-dependent manner. This effect does not require chemical conjugation of the drugs to the peptide. Systemic injection of iRGD improved the therapeutic index of various drugs, including small molecules (doxorubicin), nanoparticles (nab-paclitaxel and doxorubicin liposomes), and monoclonal antibodies (trastuzumab). The combination therapy provided equivalent or better anti-tumor efficacy at a lower dose of the drug, reducing toxicity. The iRGD-mediated enhancement in drug penetration was observed in multiple tumor models and with different drug sizes and chemical properties. The study suggests that co-administering iRGD may be a valuable approach to enhance the efficacy of anti-cancer drugs while reducing side effects.