Therapeutic application of IL-12 for cancer therapy

Interleukin-12 (IL-12) is a pleiotropic pro-inflammatory cytokine with potent antitumour activity and has been extensively explored as a candidate for cancer immunotherapy. However, its clinical development has been severely limited by the substantial systemic toxicities observed following systemic administration of recombinant IL-12. Nevertheless, the capacity of IL-12 to remodel the immunosuppressive tumour microenvironment (TME) by enhancing immune effector cell activation, proliferation, and infiltration, as well as by shifting suppressive immune cells toward a proinflammatory phenotype, underscores the need to engineer safe delivery strategies that confine cytokine activity to the tumour site. Herein, this review provides a broad and updated overview of diverse strategies for targeted IL-12 delivery to tumours. Specifically, we focus on immunocytokines, adoptive T-cell therapies, and biodegradable polymeric microspheres, while also briefly touching on protein-engineering and nanotechnology-based approaches. By reviewing their modes of action and comparing their benefits and challenges, we illustrate how modern engineering approaches have the potential to overcome the historical barriers to IL-12 therapy while preserving its potent and pleiotropic antitumour functions. Although numerous IL-12-based platforms have recently emerged, an integrative framework that connects advances across diverse engineering modalities has been lacking. Finally, we consider how combination strategies incorporating multiple therapeutic components may enable the safe deployment of IL-12 while fully realising its antitumour potential.