Immunotherapy has fundamentally reshaped the treatment landscape of gastrointestinal (GI) cancers. However, now that PD-1/PD-L1 inhibitors have been firmly established as standards of care, the key challenge facing clinical research is how to further overcome the current efficacy plateau. This has driven research into a “deep-water zone,” where novel strategies—such as next-generation TIGIT inhibitors, cancer vaccines, and T-cell engagers—are actively being explored.