Advancing interleukin-21 in cancer immunotherapy: Mechanisms of action and clinical translation

Vollständiger Abstract

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Interleukin-21 (IL-21) is a pleiotropic cytokine that coordinates both adaptive and innate immune responses. It enhances the cytotoxic activity of CD8+ T cells and natural killer cells, regulates the suppressive function of regulatory T cells, and promotes B cell-mediated antibody production, thereby showing therapeutic potential in antitumor immunity. Current evidence suggests that IL-21 can postpone or reverse T cell depletion by downregulating inhibitory receptors such as programmed cell death protein 1 and T cell immunoglobulin and mucin domain-containing protein 3 and reducing levels of the transcription factor TOX. This implies that combining IL-21 with immune checkpoint inhibitors or chimeric antigen receptor T cell therapies may produce synergistic effects. IL-21 encounters significant clinical translation challenges, particularly its limited in vivo half-life and systemic toxicity that constrain dosing. Researchers are exploring sophisticated engineering approaches to mitigate these constraints. Strategies include developing prolonged-activity IL-21 variants or tumor-targeted formulations through protein engineering, alongside creating advanced delivery systems that minimize biodistribution and reduce unintended effects. This review synthesizes IL-21’s biological roles and molecular pathways in anti-tumor immunity, examines developments in combining IL-21 with both conventional and novel immunotherapeutic approaches, and assesses current barriers to clinical translation. We then propose innovative molecular engineering and delivery mechanisms that could potentially enhance safety and efficacy of IL-21-based combination therapies in oncology.