Natural killer (NK) cells have long been viewed as a homogeneous population of innate immune cells that provide rapid, nonspecific defense against tumors and infections. However, a comprehensive review published in Cancer Biology & Medicine (April 2026) by researchers from Northwest University and Xijing Hospital, Fourth Military Medical University in China, demonstrates that the tumor microenvironment (TME) does not merely suppress NK cells—it actively sculpts them into functionally distinct subsets with specialized roles. This finding challenges the traditional binary classification of NK cells and opens new avenues for designing more precise cancer immunotherapies.
The review, titled "Tumor microenvironment-driven natural killer cell diversity: mechanisms and therapeutic opportunities," synthesizes emerging evidence on three major subsets: tumor-infiltrating natural killer (TiNK) cells, tissue-resident natural killer (TrNK) cells, and adaptive natural killer cells. Each subset responds differently to microenvironmental signals such as hypoxia, metabolic stress, and immune checkpoint molecules, revealing a dynamic and interconnected network rather than isolated populations.
TiNK cells, recruited from the bloodstream, often become dysfunctional within tumors. They downregulate activating receptors like NKG2D and NKp30 while upregulating inhibitory checkpoints including PD-1, TIGIT, and NKG2A. Their metabolism also falters, with impaired glycolysis and mitochondrial respiration. In contrast, TrNK cells permanently reside in specific organs and express residency markers such as CD69 and CD103. Their functional plasticity allows them to either suppress tumors or, under certain conditions, adopt pro-tumorigenic roles. The most striking finding involves adaptive NK cells, which develop memory-like features in response to human cytomegalovirus infection or cytokine pre-activation with IL-12, IL-15, and IL-18. These cells exhibit enhanced antibody-dependent cellular cytotoxicity (ADCC) and can persist as potent, long-lasting effectors.
The clinical implications are substantial. TiNK cell abundance correlates with prolonged survival in gastric, colorectal, and lung cancers, making it a promising prognostic biomarker. TrNK signatures predict better immunotherapy responses across multiple cancer types. Adaptive NK cells—particularly cytokine-induced memory-like natural killer (CIML-NK) cells—have shown encouraging results in early-phase trials, with a 44% remission rate in acute myeloid leukemia patients and persistence exceeding three months after infusion.
Emerging therapeutic strategies include chimeric antigen receptor (CAR)-NK cell engineering, immune checkpoint blockade targeting NKG2A and TIGIT, metabolic modulators such as GPR34 inhibitors, and combination approaches pairing NK cells with cryoablation, radiotherapy, or targeted drugs like sorafenib. Next-generation platforms like CRISPR-Cas9 gene editing, induced pluripotent stem cell-derived NK cells, and NK cell-derived extracellular vesicles are also advancing toward clinical translation.
The authors emphasize that understanding the molecular rules governing NK cell fate within tumors is critical. "If we can learn to nudge these cells toward the right fate, we might be able to design therapies that are far more effective than what we have now," they stated. This review underscores the importance of moving beyond traditional classifications to harness the full potential of NK cells in cancer treatment. For more details, the full study is available at https://doi.org/10.20892/j.issn.2095-3941.2025.0829. Additionally, related innovations can be explored at http://chuanlink-innovations.com.
