The IL-6/JAK/STAT3 pathway is hyperactivated in many cancers, contributing to poor prognosis by promoting tumor growth, invasion, metastasis, and suppressing antitumor immunity. Targeting this pathway offers therapeutic benefits by inhibiting tumor cell growth and enhancing antitumor immunity. FDA-approved agents targeting IL-6, IL-6R, or JAKs are used for inflammatory conditions and myeloproliferative neoplasms, and are being evaluated in hematologic and solid tumors. Novel inhibitors, including STAT3-selective agents, are under development. Preclinical and clinical studies are ongoing to evaluate the efficacy of these agents. The pathway is also involved in immune cell function, with STAT3 hyperactivation in immune cells leading to immunosuppression. Combining IL-6/JAK/STAT3 inhibitors with immune-checkpoint inhibitors may enhance antitumor efficacy. IL-6 signaling occurs via classic and trans-signaling pathways, with trans-signaling playing a key role in the tumor microenvironment. JAKs mediate STAT3 activation, which is crucial for tumor progression and immunosuppression. STAT3 is hyperactivated in many cancers and is regulated by various mechanisms, including miRNAs. Inhibitors of STAT3, such as small molecules and decoy oligonucleotides, are being developed. Combination therapies targeting IL-6/JAK/STAT3 and immune checkpoints show promise in improving treatment outcomes. Future research aims to identify biomarkers for personalized treatment and optimize combination strategies.The IL-6/JAK/STAT3 pathway is hyperactivated in many cancers, contributing to poor prognosis by promoting tumor growth, invasion, metastasis, and suppressing antitumor immunity. Targeting this pathway offers therapeutic benefits by inhibiting tumor cell growth and enhancing antitumor immunity. FDA-approved agents targeting IL-6, IL-6R, or JAKs are used for inflammatory conditions and myeloproliferative neoplasms, and are being evaluated in hematologic and solid tumors. Novel inhibitors, including STAT3-selective agents, are under development. Preclinical and clinical studies are ongoing to evaluate the efficacy of these agents. The pathway is also involved in immune cell function, with STAT3 hyperactivation in immune cells leading to immunosuppression. Combining IL-6/JAK/STAT3 inhibitors with immune-checkpoint inhibitors may enhance antitumor efficacy. IL-6 signaling occurs via classic and trans-signaling pathways, with trans-signaling playing a key role in the tumor microenvironment. JAKs mediate STAT3 activation, which is crucial for tumor progression and immunosuppression. STAT3 is hyperactivated in many cancers and is regulated by various mechanisms, including miRNAs. Inhibitors of STAT3, such as small molecules and decoy oligonucleotides, are being developed. Combination therapies targeting IL-6/JAK/STAT3 and immune checkpoints show promise in improving treatment outcomes. Future research aims to identify biomarkers for personalized treatment and optimize combination strategies.