The CREM-IL-15 axis: decoding the persistence-exhaustion paradox in NK cell immunotherapy

Natural killer (NK) cells are critical components of the innate immune system, renowned for their ability to recognize and eliminate malignant and infected cells without prior sensitization. NK cell immunotherapy encompasses various approaches, including adoptive transfer of ex vivo expanded NK cells, cytokine stimulation to enhance their activity, and genetic modifications to improve persistence and specificity. CREM is a cAMP-responsive transcription factor that modulates gene expression in response to receptor- and cytokine-driven signaling. Recent evidence now shows that IL-15 and CAR stimulation rapidly induce CREM in activated NK cells. Rafei (Nature 643:1076-1086, 2025) further demonstrated in CAR-NK models that CREM functions as a regulatory checkpoint limiting NK cell cytotoxicity and cytokine production, while its relevance in resting/native NK cells remains to be established. The CREM-IL-15 signaling axis has emerged as a pivotal regulator of NK cell biology, influencing their development, activation, and longevity. IL-15 is a critical cytokine for NK cell survival, proliferation, and functional maturation. Understanding this axis is vital, as it offers insights into mechanisms that sustain NK cell activity and those that lead to functional exhaustion, thereby informing strategies to enhance therapeutic efficacy. A central challenge in NK cell immunotherapy is balancing cellular persistence with functional exhaustion. Persistent NK cell activity is desirable for sustained tumor control; however, prolonged activation often results in cellular exhaustion characterized by diminished cytotoxicity and cytokine production. This paradox hampers the long-term success of NK cell-based treatments. The CREM-IL-15 axis plays a complex role in this dynamic, potentially promoting NK cell survival and persistence while also contributing to exhaustion under certain conditions. Deciphering the molecular underpinnings of this paradox is essential for developing interventions that maintain NK cell functionality over time, thereby improving therapeutic outcomes in cancer patients.