Understanding the cellular regulation of tumor-specific CD8⁺ T-cell responses is critical to designing improved clinical strategies for cancer immunotherapy. In this issue, Aoki and colleagues deepen our knowledge of this topic by demonstrating that transient depletion of CD4⁺ T cells in patients with gastrointestinal cancer induces remodeling of the T-cell repertoire, including clonal replacement and expansion of CD8⁺ T-cell clones shared between the blood and tumor.