Abstract: Primary resistance, acquired resistance and immune-related adverse events continue to limit the clinical application value of immune checkpoint blockade (ICB). Natural products provide complementary therapeutic strategies to overcome these limitations due to their unique chemical diversity and inherent multi-target pharmacological properties. This review systematically reviews the research progress in the field of natural product-mediated tumor immune checkpoint regulation from 2020 to 2026, and discusses its role in multi-pathway synergy, protein homeostasis intervention and immune microenvironment remodeling from the perspective of medicinal chemistry. This paper also evaluated the key obstacles in translational medicine, including target resolution problems and poor pharmacokinetic characteristics, and analyzed them in combination with relevant mechanistic insights. This review covers more than 100 natural products and 10 immune checkpoints, and takes candidate drugs such as Icaritin and YIV-906 in the clinical research and development stage as examples to clarify their translational medicine application pathways. Emerging technologies, including artificial intelligence-assisted target prediction and proteolysis-targeting chimera (PROTAC) design, are discussed as potential accelerators for advancing natural products toward next-generation immunotherapeutics.