The addition of immune checkpoint blockade (ICB) to the standard of care for advanced gastroesophageal cancer (GEC) confers long-term benefit in a subset of patients. However, most patients remain refractory to therapy. In this study, we aim to elucidate the mechanisms of response and resistance to combination ICB and to identify new targets for immunotherapy, with a particular focus on LINE-1 repeat elements which show prominent activity in GEC. We performed multi-omic characterization of pre- and on/post-treatment samples from early progressors and long-term responders, comprising long-read whole genome sequencing, RNA-seq and multiplex immunofluorescence. This integrative analysis revealed a potential role for LINE-1 repeat elements in shaping the tumor microenviroment. High LINE-1 burden was associated with chromosomal instability, chronic cGAS-STING activation, and decreased CD8 T cell/Treg ratio. Using GEC cell lines, we showed that nucleoside reverse transcriptase inhibitors (NRTi) can partially inhibit constitutive cGAS-STING stimulation, likely through inhibition of cytosolic LINE-1 reverse transcription activity. In addition, we identified that LINE-1-derived HLA-I peptides can elicit strong CD8 T cell responses in vitro, and can be shared across patients. These findings support the therapeutic potential of combining NRTi treatment combined with LINE-1 targeted vaccines in GEC.