<p>Interleukin-18 (IL-18) is a pleiotropic cytokine of the IL-1 family that has an important role in antitumour and antiviral immunity. Growing interest in its therapeutic potential has led researchers to explore strategies that harness IL-18 to modulate the tumour microenvironment. For example, engineered T cells are being armoured with IL-18 to enhance adoptive cell therapies and strengthen other immunotherapy approaches. As these strategies move towards clinical application, a key translational challenge is identifying the molecular mechanisms that influence treatment response and resistance, crucial for guiding trial design and patient selection across tumour types. This Review revisits the fundamental biology of IL-18, including its origins, cellular sources and regulatory networks, particularly those involving IL-18 binding protein (IL-18BP) and IL-37. We discuss how IL-18 promotes interferon-γ&#xa0;(IFNγ) production within the tumour microenvironment, supporting M1-like macrophage polarization, CD8⁺ cytotoxic T cell and CD4⁺ T helper 1 cell responses, natural killer cell activity and durable T cell memory. We also discuss preclinical models of IL-18 delivery, including dendritic cell platforms and cellular therapies, and highlight emerging strategies such as IL-18BP blockade and IL-18-secreting CAR T cells. Finally, we review results from early clinical studies and outline key challenges for translation, including the dual protumour and antitumour roles of IL-18.</p>