biostudies-literatureNayak INIAID NIH HHSNational Institutes of HealthCRUK Cancer Research UKNIH HHS192-212https://www.ebi.ac.uk/biostudies/studies/S-EPMC11792776biostudies-literatureUnknown103(2)Natural killer (NK) cells are emerging agents for cancer therapy. Several different cytokines are used to generate NK cells for adoptive immunotherapy including interleukin (IL)-2, IL-12, IL-15 and IL-18 in solution, and membrane-bound IL-21. These cytokines drive NK cell activation through the integration of signal transducers and activators of transcription (STAT) and nuclear factor-kappa B (NF-κB) pathways, which overlap and synergize, making it challenging to predict optimal cytokine combinations for both proliferation and cytotoxicity. We integrated functional assays for NK cells cultured in a variety of cytokine combinations with mathematical modeling using feature selection and mechanistic regression models. Our regression model successfully predicts NK cell proliferation for differImmunology and cell biologyModeling the response to interleukin-21 to inform natural killer cell immunotherapy.PMC11792776HUNTER HCC expediter network award (C9380/A18084)R56 AI146581R01 AI146581R01-AI 146581R01‐AI 146581Biondo RFulton RJKhakoo SIMoker NNayak IStewart WCZhang CDas JfalseModeling the response to interleukin-21 to inform natural killer cell immunotherapy.Natural killer (NK) cells are emerging agents for cancer therapy. Several different cytokines are used to generate NK cells for adoptive immunotherapy including interleukin (IL)-2, IL-12, IL-15 and IL-18 in solution, and membrane-bound IL-21. These cytokines drive NK cell activation through the integration of signal transducers and activators of transcription (STAT) and nuclear factor-kappa B (NF-κB) pathways, which overlap and synergize, making it challenging to predict optimal cytokine combinations for both proliferation and cytotoxicity. We integrated functional assays for NK cells cultured in a variety of cytokine combinations with mathematical modeling using feature selection and mechanistic regression models. Our regression model successfully predicts NK cell proliferation for differ2025-01-01T00:00:00Z2025 Feb2026-05-02T03:45:26.295Z2025-04-04T07:26:03.623ZS-EPMC117927763986534410.1111/imcb.12848