Gastrointestinal (GI) cancer is one of the common causes of cancer-related death worldwide. Chemotherapy and/or immunotherapy are the current treatments, but some patients do not derive clinical benefits. Recently, studies from cancer molecular subtyping have revealed that tumor molecular biomarkers may predict the immunotherapeutic response of GI cancer patients. However, the therapeutic response of patients selected by the predictive biomarkers is suboptimal. The tumor immune-microenvironment apparently plays a key role in modulating these molecular-determinant predictive biomarkers. Therefore, an understanding of the development and recent advances in immunotherapeutic pharmacological intervention targeting tumor immune-microenvironments and their potential predictive biomarkers will be helpful to strengthen patient immunotherapeutic efficacy. The current review focuses on an understanding of how the host-microenvironment interactions and the predictive biomarkers can determine the efficacy of immune checkpoint inhibitors. The contribution of environmental pathogens and host immunity to GI cancer is summarized. A discussion regarding the clinical evidence of predictive biomarkers for clinical trial therapy design, current immunotherapeutic strategies, and the outcomes to GI cancer patients are highlighted. An understanding of the underlying mechanism can predict the immunotherapeutic efficacy and facilitate the future development of personalized therapeutic strategies targeting GI cancers.
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