Targeting Tc17 cell differentiation via the IL-6/JAK1/STAT3 signaling axis to attenuate immune checkpoint inhibitor-related colitis and promote tumor immunity

Immune checkpoint inhibitor-related colitis (IRC) is one of the most common immune-related adverse events, yet its underlying mechanisms remain unclear and treatments lack precision targeting. This study aims to elucidate the immune cell infiltration characteristics and regulatory mechanisms in IRC, providing new strategies for clinical intervention. The immunological profile of peripheral blood was analyzed in IRC patients. Single-cell RNA sequencing, Western blotting, and flow cytometry were employed to examine key T cell subsets and regulatory mechanisms. Additionally, we evaluated the effects of targeting this pathway on IRC and antitumor immunity in liver tumor and melanoma models. IRC patients exhibited significantly elevated peripheral blood CD8 + T cell proportions and IL-17 A levels. Single-cell transcriptomic analysis of colon from IRC mice revealed significant T cell infiltration, particularly expansion of Tc17 cells, along with enrichment of the JAK/STAT signaling pathway in this subset. In vitro, IL-6 drives CD8 + T cell differentiation into Tc17 cells via the JAK1/STAT3 axis. IL-6/JAK1 blockade not only suppressed Tc17 differentiation but also induced the conversion of CD8 + T cells into FOXP3 + CD8 + Tregs. In vivo, targeting the IL-6/JAK1 reduced the proportion of Tc17 cells, increased that of Tregs in the colon, and effectively alleviated colonic inflammation. In the liver tumor and melanoma models, inhibition of IL-6/JAK1 concurrently alleviated IRC and synergistically enhanced the antitumor efficacy of ICIs. Targeted blockade of IL-6/JAK1/STAT3 axis suppresses Tc17 differentiation and drives the conversion of CD8 + T cells into FOXP3 + Tregs, ameliorating IRC while synergistically enhancing ICI-mediated antitumor immunity. This provides a new avenue for the therapeutic decoupling of antitumor immunity and autoimmune toxicity.