NK Cells Differentiate Into 3 Types Within Tumors, Opening New Paths for Immunotherapy

A study has found that, within tumors, natural killer (NK) cells differentiate into three distinct functional states, rather than the two types previously recognized.

According to Azer Life Science on the 7th (local time), researchers from Northwest University in China and Xijing Hospital of the Fourth Military Medical University published a comprehensive review in the April 2026 issue of the international journal Cancer Biology & Medicine, describing how the tumor microenvironment differentiates NK cells into three subpopulations. The Chinese Anti-Cancer Association introduced the findings.

Based on studies of blood, NK cells have traditionally been classified into just two groups: those responsible for cytokine production and those that directly kill cells. But inside tumors, hypoxia, metabolic stress and immune checkpoint molecules can drive cells into entirely different states, including exhaustion, tissue residency and memory-like characteristics.

The researchers identified three subpopulations: tumor-infiltrating NK (TiNK) cells, tissue-resident NK (TrNK) cells and adaptive NK cells. After moving from the blood into tumors, TiNK cells show reduced expression of the activating receptors NKG2D and NKp30 and increased expression of inhibitory checkpoints such as PD-1, TIGIT and NKG2A, resulting in impaired function. Glycolysis and mitochondrial respiration also weaken.

By contrast, TrNK cells reside in specific organs and express markers such as CD69 and CD103. Depending on the circumstances, they can suppress tumors or, conversely, promote tumor growth.

Adaptive NK cells are considered the most notable finding. In response to human cytomegalovirus (HCMV) infection, they acquire an NKG2C-positive phenotype and enhanced antibody-dependent cellular cytotoxicity (ADCC), or are preactivated with interleukin-12 (IL-12), IL-15 and IL-18 and reprogrammed into potent effector cells that persist over time.

The researchers said, “The conventional view of NK cells as just two types does not hold up when you look inside tumors. The microenvironment differentiates cells into distinct states: Some become impaired, some stay in place, and some grow more potent over time.”

The findings also have significant clinical implications. TiNK cell abundance is associated with longer survival in gastric, colorectal and lung cancers, making it a promising prognostic biomarker. TrNK cell signals serve as indicators that predict response to immunotherapy and favorable outcomes across several cancer types.

Among adaptive NK cells, cytokine-induced memory-like NK (CIML-NK) cells induced remission in 44% of patients with acute myeloid leukemia in early clinical trials and persisted in the body for more than 3 months after infusion.

Proposed new treatment strategies include engineering chimeric antigen receptor (CAR)-NK cells, blocking immune checkpoints targeting NKG2A and TIGIT, and using metabolic modulators such as GPR34 inhibitors. Combination therapies pairing NK cells with cryoablation, radiation therapy or targeted drugs such as sorafenib have also been discussed.

The researchers added that next-generation platforms include CRISPR-Cas9 gene editing, induced pluripotent stem cell-derived NK cells and NK cell-derived extracellular vesicles, and that research toward clinical application is underway.