Gastroesophageal adenocarcinoma (GEAC) is characterized by low survival rates and limited therapeutic possibilities. GEAC heterogeneity, in terms of molecular complexity and anatomical distribution, makes the selection of a more personalized treatment challenging. Immunotherapy approaches have been shown to be only partially effective, and their optimal use is hindered by the limited knowledge of the immune response during GEAC progression. The aim of this proposal is to improve the current understanding of the immune response dynamics at different stages of GEAC evolution, integrating cutting-edge techniques such as high dimensional flow cytometry, RNA sequencing, proteomics, multiparametric imaging and ex vivo functional assays. We have designed an integrative strategy with 3 independent projects supported by preliminary data, competent personnel and supporting host institution. Importantly, we have established a close collaboration with leading clinicians at Karolinska University Hospital. We will use samples from two independent GEAC cohorts and to extensive clinical data. Necessary tthical permits have already been granted. In summary, we plan to introduce the study of tumor-infiltrating inflammatory signatures in the classification of GEAC patients, with an inherent impact on clinical practice and therapy selection. In parallel, we will deepen the mechanisms of endogenous antitumor immunity, exploring the potential relevance of a novel subset of unconventional T cells.