The key role of immunomodulatory cytokines for the development of novel NK cell-based cancer therapies.

Cytokines are crucial modulators of immune responses and have emerged as key components in cancer immunotherapy, particularly concerning Natural Killer (NK) cells. Indeed, the administration of these cytokines have demonstrated significant therapeutic potential in clinical settings. For instance, interleukin-2 (IL-2) has shown efficacy in melanoma and renal cell carcinoma, enhancing anti-tumor immunity but often associated with dose-limiting toxicities. IL-12 has been linked to improved survival rates in various solid tumors by stimulating Th1 responses and activating NK cells. Additionally, IL-15 has gained recognition for its ability to enhance NK cell proliferation and persistence, translating into favorable clinical outcomes in hematological malignancies such as acute myeloid leukemia (AML). Remarkably, cytokines can act synergistically providing stronger effects, and recent advancements have led to the identification of cytokine-induced memory-like NK (CIML-NK) cells. Despite these advancements, significant challenges persist in the translation of cytokine and NK cell therapies into routine clinical practice. The short half-life of recombinant cytokines poses limitations on their effectiveness, requiring high doses that can lead to severe side effects. Additionally, the complexities involved in the large-scale production of cytokines and the development of GMP-grade NK cell-therapies must be overcome. Innovative delivery systems, such as heterodimeric fusion proteins, oncolytic viruses and cytokine gene therapy, have emerged to address these issues, yet further research is needed to optimize these approaches. Collectively, this review underscores the importance of cytokines in harnessing the full potential of NK cells for cancer immunotherapy, and ongoing efforts that aim to optimize cytokine delivery strategies and enhance NK cell manufacturing processes.