This review focuses on the development and application of polymer-based drug delivery systems (DDSs) for cancer therapy. It highlights the challenges and advancements in enhancing the pharmacokinetic and therapeutic potential of chemotherapeutic agents through the use of natural and synthetic polymers. The review discusses the barriers that impact the success of chemotherapy, such as off-target effects and dose-limiting toxicities, and explores recent developments in polymer-based DDSs that aim to overcome these challenges. **Key Points:** 1. **Natural Polymers:** - **Chitosan:** A biocompatible and biodegradable polysaccharide with cationic properties, enhancing mucoadhesion, transfection, and permeation. - **Hyaluronic Acid (HA):** An anionic linear polymer with a wide range of molecular weights, used for its affinity to overexpressed receptors on cancer cells and its ability to prolong circulation half-life. - **Alginate:** A naturally occurring polysaccharide with good solubility and water retention capacity, suitable for oral administration and controlled drug release. - **Cellulose:** The most abundant structural polymer, known for its mechanical strength and biodegradability, used in various administration routes. - **Gelatin:** Derived from collagen, it is a low-toxicity, biocompatible, and biodegradable polymer, effective for delivering hydrophilic and lipophilic drugs. - **Dextran:** A neutral polysaccharide with high solubility and biodegradability, suitable for oral delivery and co-delivering small anticancer drugs with antibodies. 2. **Synthetic Polymers:** - **Hydrophobic/Hydrophilic and Block Copolymers:** Examples include PLGA, PEG, and PEI, which are FDA-approved for long-acting release and have been used to encapsulate various anticancer drugs. - **Dendrimers and Hyperbranched Polymers (HBPs):** Known for their three-dimensional structures and high stability, they are effective for targeted drug delivery and gene therapy. - **pH-Responsive Polymers:** Utilize the acidic microenvironment around tumors to selectively release chemotherapeutics, improving in vivo efficacy. The review emphasizes the potential of polymer-based DDSs to enhance the effectiveness and safety of cancer treatments by overcoming the limitations of traditional chemotherapy, such as reduced systemic toxicity and improved targeting of therapeutic agents to tumor sites.This review focuses on the development and application of polymer-based drug delivery systems (DDSs) for cancer therapy. It highlights the challenges and advancements in enhancing the pharmacokinetic and therapeutic potential of chemotherapeutic agents through the use of natural and synthetic polymers. The review discusses the barriers that impact the success of chemotherapy, such as off-target effects and dose-limiting toxicities, and explores recent developments in polymer-based DDSs that aim to overcome these challenges. **Key Points:** 1. **Natural Polymers:** - **Chitosan:** A biocompatible and biodegradable polysaccharide with cationic properties, enhancing mucoadhesion, transfection, and permeation. - **Hyaluronic Acid (HA):** An anionic linear polymer with a wide range of molecular weights, used for its affinity to overexpressed receptors on cancer cells and its ability to prolong circulation half-life. - **Alginate:** A naturally occurring polysaccharide with good solubility and water retention capacity, suitable for oral administration and controlled drug release. - **Cellulose:** The most abundant structural polymer, known for its mechanical strength and biodegradability, used in various administration routes. - **Gelatin:** Derived from collagen, it is a low-toxicity, biocompatible, and biodegradable polymer, effective for delivering hydrophilic and lipophilic drugs. - **Dextran:** A neutral polysaccharide with high solubility and biodegradability, suitable for oral delivery and co-delivering small anticancer drugs with antibodies. 2. **Synthetic Polymers:** - **Hydrophobic/Hydrophilic and Block Copolymers:** Examples include PLGA, PEG, and PEI, which are FDA-approved for long-acting release and have been used to encapsulate various anticancer drugs. - **Dendrimers and Hyperbranched Polymers (HBPs):** Known for their three-dimensional structures and high stability, they are effective for targeted drug delivery and gene therapy. - **pH-Responsive Polymers:** Utilize the acidic microenvironment around tumors to selectively release chemotherapeutics, improving in vivo efficacy. The review emphasizes the potential of polymer-based DDSs to enhance the effectiveness and safety of cancer treatments by overcoming the limitations of traditional chemotherapy, such as reduced systemic toxicity and improved targeting of therapeutic agents to tumor sites.