The mechanisms underlying the efficacy and toxicity of anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) therapy are incompletely understood. First, by studying the programming of responding PD-1+CD8+ T (Tresp) cell populations from patients with advanced melanoma, we identified differential programming of Tresp cells in response to combination therapy, from an exhausted toward a more cytotoxic effector program. This effect does not occur with anti-PD-1 monotherapy. Single-cell transcriptome and T cell receptor repertoire analysis was used to identify altered effector programming of expanding PD-1+CD8+ T cell clones with distinct regulon usage, STAT1 and STAT3 utilization and antitumor specificity connected to interleukin (IL)-21 signaling in combination and anti-CTLA-4 monotherapy. Therapeutic efficacy of CTLA-4 blockade was lost in B16F10 melanoma models with either Il21r- deficiency or anti-IL-21 receptor blockade. Together, these results show how IL-21 signaling to TResp is critical for anti-CTLA-4-based checkpoint therapies and highlight major signaling differences to anti-PD-1 monotherapy. Nevertheless, checkpoint therapy induces significant and potential life-threatening immune-mediated side-effects, such as the liver. By spatial single-cell and transcriptomic analysis of the inflamed livers of checkpoint therapy induced-hepatitis (ICI-Hep) and spontaneous autoimmune hepatitis, we identify responding T cells as hallmarks of pathological liver inflammation and identify distinct interaction partners and therapeutically targetable signaling pathways. The presentation highlights differential pathways mediating the reprogramming of exhausted T cells downstream of checkpoint therapy.