<p>The stimulator of interferon genes (STING) pathway is a key target in cancer immunotherapy. Although STING agonists have shown promise in preclinical models, this has not been translated into the clinic. There is an incomplete understanding, particularly in non-murine models, of dose–toxicity and dose–efficacy relationships. Moreover, the ideal dose and delivery kinetics to achieve an optimal response and to avoid overt or chronic inflammation, as well as the appropriate combination therapy, remains unclear. These challenges are compounded by the delivery barriers, including short circulatory half-life, poor cell internalization and non-specific tissue uptake — all of which hinder their clinical application. Biomaterial-based delivery systems offer a powerful means to overcome these hurdles, expanding the therapeutic window of STING agonists and providing mechanistic insights into immune cell interactions that dictate therapeutic outcomes. In this Review, we discuss the current landscape of STING agonists in cancer and how biomaterial platforms can be leveraged to enhance their therapeutic benefits while minimizing toxicity. We also explore biomaterials that can improve combinatorial therapies and regimens that overcome the immunosuppressive tumour microenvironments. Additionally, we investigate biomaterial strategies used to understand the biological mechanisms and long-term effects of STING-based therapies.</p>