Abstract: The advent of immunotherapy has revolutionized traditional paradigms in cancer treatment and has demonstrated significant clinical benefits across various malignancies. However, this progress is accompanied by emerging challenges, such as immune evasion and low response rates to immunotherapy. As an immunomodulatory molecule, Zymogen Granule Protein 16 (ZG16) plays a crucial role in immunotherapy by inhibiting the binding of programmed death 1 (PD-1) to its ligand PD-L1, thereby preventing immune evasion and restoring the immune system's ability to recognize and eliminate tumor cells. ZG16 is downregulated in multiple gastrointestinal tumors, and its regulatory mechanisms vary depending on the tumor type. Studies have confirmed that ZG16 binds to PD-L1 and promotes its degradation, thereby alleviating T‑cell suppression, reinstating the recognition of tumor cells, and exerting antitumor effects. Moreover, ZG16 expression is closely associated with patient prognosis, and it has been identified as a favorable prognostic marker in colorectal cancer. This article provides a systematic overview of the structural characteristics, expression regulation mechanisms, and anti-tumor immune functions of ZG16.