Cytokines are the master communicators of the immune system, acting as potent signaling proteins that direct cellular traffic, activate threat responses and maintain balance.(p1) The ability of specific cytokines to orchestrate powerful and coordinated antitumor immune responses has positioned them as a compelling, albeit challenging, class of cancer therapeutics.(p1),(p2) By stimulating key effector cells like T cells and natural killer (NK) cells, or by modulating the tumor microenvironment (TME) to be less hospitable to cancer, these molecules offer the potential to turn the patient’s own immune system into a precision weapon against malignancies.(p2) Landmark approvals of high-dose recombinant interferon-alpha (IFN-α) for hairy cell leukemia(p3) and, later, high-dose interleukin (IL)-2 for metastatic melanoma and renal cell carcinoma,(p4) established their clinical potential. These first-generation cytokine therapies, while only effective in a minority of patients, provided definitive proof-of-concept: systemic administration of a cytokine could induce durable, complete remissions in some patients with advanced cancers. These early successes ignited decades of intense research and clinical investigation into a broad pipeline of other immune-stimulating candidates, including IL-12,(p5) IL-15(p6) and various interferons.(p7) Notwithstanding these early successes and substantial research efforts, the clinical translation of most cytokine candidates has been unsuccessful. The primary pharmacological liabilities, which have persisted throughout the field’s history, are their intrinsically poor pharmacokinetic profiles, characterized by a short circulating half-life, and their potent, pleiotropic signaling, which results in mechanism-based systemic toxicities.(p1),(p2)

The severe toxicity and poor pharmacokinetics of systemic antitumor cytokine therapy have prompted a shift toward sophisticated, protein-based delivery systems.(p8) A new therapeutic modality: mRNA, presents a disruptive alternative to conventional protein expression (Figure 1). mRNA technology enables the in situ synthesis of therapeutic proteins, effectively turning the patient’s body into a localized drug factory.(p9),(p10) When applied to antitumor cytokine therapy, this platform offers the tantalizing prospect of generating high local concentrations within the TME while avoiding the systemic exposure that causes toxicity. The mRNA manufacturing process offers significant advantages over complex, multi-step recombinant cytokine production, facilitating rapid research iteration and subsequent large-scale manufacturing. This review evaluates the potential of mRNA technology as an innovative and powerful platform for antitumor cytokine production and delivery, analyzing its advantages over traditional recombinant proteins and engineered cytokines and discussing the challenges that must be addressed to realize its clinical promise.