Restoration of deficient IL-15 signaling enhances innate lymphoid cell immunity in brain metastasis

McMullen, T. P.; Naef, P.; Zagni, E.; Tian, L.; Zhao, E.; Wechter, N.; Longworth, A. J.; Adam, I.; Insua-Rodriguez, J.; Savage, H.; Hur, I.; Garcia, S. A.; Ma, D.; Liew, M. H.; Mallya, S.; Kessenbrock, K.; O'Sullivan, T. E.; Mohyeldin, A.; Yu, J.; Lawson, D. A.

doi:10.64898/2026.10.02.756334

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bioRxiv · 10.64898/2026.10.02.756334

Restoration of deficient IL-15 signaling enhances innate lymphoid cell immunity in brain metastasis

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Abstract

Natural killer (NK) cells and type 1 innate lymphoid cells (ILC1s), collectively known as group 1 innate lymphoid cells (ILCs), are critical mediators of anti-tumor immunity, yet their role in brain metastasis remains poorly defined. Using single-cell RNA sequencing and functional depletion models, we show that group 1 ILCs fail to provide adequate tumor control in breast cancer brain metastasis (BCBM). In contrast to the liver, where diverse, functionally competent group 1 ILC populations facilitate excellent metastatic control, group 1 ILCs in BCBM show limited diversity and profound tissue-specific dysfunction such that their depletion had no effect on tumor burden despite modest parenchymal infiltration. We attribute this group 1 ILC dysfunction to severely restricted IL-15 availability, with IL-15R protein detected at 500-fold lower concentration in the brain than in the liver. Local IL-15 complex administration restored group 1 ILC accumulation, cytotoxicity, and tissue residency, significantly reducing brain metastatic burden independent of T cells. Intracranial delivery of IL-15-secreting induced pluripotent stem-cell-derived (iPSC)-NK cells, already in clinical testing for non-small cell lung cancer, significantly reduced tumor burden. Collectively, these findings reveal how tissue-specific differences in cytokine availability shape group 1 ILC population diversity and disease response, establishing localized IL-15 signaling as a compelling strategy to unlock innate immunity against intracranial malignancies.

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McMullen, T. P., Naef, P., Zagni, E., Tian, L., Zhao, E., Wechter, N., Longworth, A. J., Adam, I., Insua-Rodriguez, J., Savage, H., Hur, I., Garcia, S. A., Ma, D., Liew, M. H., Mallya, S., Kessenbrock, K., O'Sullivan, T. E., Mohyeldin, A., Yu, J., Lawson, D. A.. 2026-10-10. Restoration of deficient IL-15 signaling enhances innate lymphoid cell immunity in brain metastasis. https://doi.org/10.64898/2026.10.02.756334

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