The field of immuno-oncology has gained great interest. Novel immune-enhancing treatment modalities against cancer have been approved for some solid cancers, especially in malignant melanomas and non-small-cell lung cancer, showing promising results on patient survival. Research in the area of immunotherapy is still ongoing and yet to be approved for some gastrointestinal cancers. With the continuous advances in immuno-oncology, immunodiagnostic tests, in which the immune-related features of a malignant tumor are characterized, play a crucial role. Immunodiagnosis seek to identify both local and systemic characteristics of a malignancy. Immunodiagnostic tests may assist in cancer prognostication and in the selection of oncological treatment for patients with cancer. For instance, the density of tumor-infiltrating lymphocytes (TILs), especially CD8+ T cells have been correlated with improved prognosis in patients with gastrointestinal (GI) cancers. Likewise, a high infiltration of FoxP3+ lymphocytes has been associated with poor prognosis in different cancers, including upper GI cancers. The role of programmed death-ligand 1 (PD-L1) and tumor mutational burden (TMB) in upper GI cancers are yet to be considered as standard-of care biomarkers for prognosis and treatment response to immune-enhancing therapies. In this chapter, novel immunodiagnostic approaches for upper GI cancers will be presented and discussed in detail. The future aspects of immuno-oncology in upper GI cancers will also be discussed. The chapter will especially focus on how the local features (in the tumor microenvironment) of upper GI cancers can be examined through immunodiagnostic tests to determine prognosis and treatment response to immunotherapy.