Gastrointestinal cancers have a high incidence and mortality rate in both sexes. Today, traditional treatments such as surgery, radiotherapy, chemotherapy, and antiangiogenic treatments are used. There has been an increase in overall survival and progression-free survival rates with the introduction of immunotherapies. Immunotherapies increase the treatment response against cancer cells by activating T lymphocytes in the body at the receptor level (acting on PD-1/PDL1 and CTLA-4 receptors). Different tests (PD-1/PD-L1 level, microsatellite instability, tumor mutation burden, and combined positive score) are currently used to determine the effectiveness of immune checkpoint inhibitors on cancer cells. Immunotherapy can be used alone or in combination with chemotherapy in gastrointestinal cancers. The benefits of the combination of a tyrosine kinase inhibitor and immunotherapy on survival and progression-free survival have been observed in clinical trials in tumors with high immune burden, such as hepatocellular cancer, and are at the forefront of chemotherapy in follow-up in current guidelines. In our chapter, we presented the effect mechanism of immunotherapy in gastrointestinal system cancers, treatment response rates, strong clinical research results, and the relationship between microbiota and immunotherapy.