# Fifty Years of Natural Killer Cells: Milestones and Future Horizons

## TL;DR

This paper reviews 50 years of natural killer (NK) cell research, highlighting key discoveries and their impact on immunology and immunotherapy.

## Contribution

The paper synthesizes historical milestones and recent advances in NK cell biology, emphasizing their translational potential in immunotherapy.

## Key findings

- NK cells were first identified through their spontaneous cytotoxicity and 'missing self' recognition mechanism.
- Advances in genetics and imaging revealed NK cell diversity and tissue specialization.
- Translational developments include engineered NK cells and checkpoint blockade strategies in clinical trials.

## Abstract

The discovery of natural killer (NK) cells stands among the fundamental milestones in modern immunology. To mark the 50‐year anniversary of the first publications on NK cells in 1975, a symposium was held at Karolinska Institutet in Stockholm, Sweden, on October 14, 2025. The symposium brought together scientists from across generations to reflect on the field's historical roots and future directions. The meeting traced NK cell research from its serendipitous beginnings with the identification of a previously unknown lymphocyte population capable of mediating spontaneous cytotoxicity to the conceptual proposal of ‘missing self’ recognition. Subsequent studies established the role of the first inhibitory receptor Ly49A. This was followed by the discovery of NK cell killer‐cell immunoglobulin‐like receptors (KIRs), along with a range of associated inhibitory and activating receptors, providing further insights into NK cell target recognition. The symposium then highlighted how advances in genetics, cell imaging and single‐cell technologies have revealed NK cell diversity, tissue specialisation and adaptive potential. It showcased insights from rare immunodeficiencies, tumour immunology, viral immunology and systems‐level analyses, underscoring NK cells' dual roles in cytotoxic defence and immune regulation. Increasingly, artificial intelligence (AI) is being leveraged in NK cell research. Translational developments described have bridged fundamental knowledge with clinical application, exemplified by current clinical studies of engineered NK cells, NK cell engagers and checkpoint blockade strategies. Together, these reflections underscored how five decades of NK cell research, rooted in seminal Scandinavian discoveries, have transformed from an unexpected observation into a cornerstone of immunotherapeutic potential.

To mark 50 years of NK cell research, a 2025 Karolinska symposium traced discoveries from spontaneous cytotoxicity and “missing self” recognition to receptor biology, cellular diversity, and translational advances, highlighting NK cells’ evolution into modern immunotherapy.