Interleukin-12 (IL-12), a powerful type 1 pro-inflammatory cytokine, demonstrates significant antitumor properties across numerous preclinical tumor models. However, the impressive antitumor efficacy demonstrated by IL-12 in preclinical studies has not been effectively reproduced in clinical researches. Clinical studies utilizing IL-12 as a treatment predominantly have shown limited efficacy in achieving sustained antitumor responses and are often accompanied by significant toxicities. Nevertheless, IL-12’s pleiotropic antitumor activity still predicts a great promising future in cancer therapy, attracting enormous cancer researchers. Efforts are underway to enhance the local accumulation of IL-12 within the tumor microenvironment while minimizing systemic exposure. In preclinical studies, diverse IL-12 delivery systems, from fusion proteins to mRNA encapsulated in nanoparticles, have demonstrated robust antitumor effects with reduced toxicity. Several IL-12 delivery approaches have recently entered the clinical stage. In this review, we mainly discuss the development of nanomedicine-associated delivery mechanisms for IL-12 in cancer therapy, emphasizing advantageous approaches to harness IL-12's antitumor properties and mitigate its adverse side effects. Display omitted •IL-12’s pleiotropic antitumor activity indicates its promising future in cancer immunotherapy.•Nanotechnology enhances local retention of IL-12 within tumor while minimizing systemic exposure.•Recent advances in clinical translation highlight the advantages of mRNA-based nanomedicine for IL-12 delivery.