Abstract: Immune checkpoint inhibitors (ICI), an immunotherapy, have an important role in the treatment of various cancers. However, ICIs induce several immune-related adverse events (irAEs). Interleukin (IL)-6 is an important inflammatory factor that promotes cancer progression and modulates the clinical application of ICIs through various mechanisms. Herein, we postulate possible mechanisms that are involved in the ICI-regulatory effects mediated by the expression of the cytokine interleukin-6 (IL-6), elucidate the effect of IL-6 on checkpoint-blockade therapy and irAEs, and summarize the role of IL-6 signaling-targeted interventions in ICIs efficacy and irAEs management.