This review discusses the challenges and strategies for improving the enhanced permeability and retention (EPR) effect in cancer treatment using nano-sized agents. Nano-sized agents offer advantages such as higher loading capacity, protection of the payload, specific targeting, and controlled release. However, their delivery to tumors is limited by the EPR effect, which depends on tumor vasculature characteristics. Factors influencing EPR include regional blood flow, vascular permeability, structural barriers, and intratumoral pressure. To enhance delivery, methods such as altering physiological conditions, modifying tumor vasculature, and killing tumor cells to reduce barriers are explored. Techniques like pharmaco-angiography, anti-angiogenic drugs, and photo-immunotherapy (PIT) are discussed. PIT, which selectively kills perivascular tumor cells, significantly enhances the EPR effect, leading to improved drug delivery. The review emphasizes the importance of optimizing nano-agent design and targeting strategies to enhance therapeutic outcomes in cancer treatment.This review discusses the challenges and strategies for improving the enhanced permeability and retention (EPR) effect in cancer treatment using nano-sized agents. Nano-sized agents offer advantages such as higher loading capacity, protection of the payload, specific targeting, and controlled release. However, their delivery to tumors is limited by the EPR effect, which depends on tumor vasculature characteristics. Factors influencing EPR include regional blood flow, vascular permeability, structural barriers, and intratumoral pressure. To enhance delivery, methods such as altering physiological conditions, modifying tumor vasculature, and killing tumor cells to reduce barriers are explored. Techniques like pharmaco-angiography, anti-angiogenic drugs, and photo-immunotherapy (PIT) are discussed. PIT, which selectively kills perivascular tumor cells, significantly enhances the EPR effect, leading to improved drug delivery. The review emphasizes the importance of optimizing nano-agent design and targeting strategies to enhance therapeutic outcomes in cancer treatment.