Natural killer (NK) cells, long considered frontline immune defenders against cancer, exhibit far more complexity inside tumors than previously understood, according to a comprehensive review published in Cancer Biology & Medicine (April 2026). The review, titled "Tumor microenvironment-driven natural killer cell diversity: mechanisms and therapeutic opportunities," shows that the tumor microenvironment does not merely suppress NK cells but actively sculpts them into specialized subsets with distinct roles, challenging the traditional binary classification that has guided the field for decades.
For years, NK cells were divided into two groups based on surface markers: one specialized for cytokine production and the other for direct killing. However, this system, derived primarily from blood studies, fails to capture how these cells behave within solid tumors. Factors such as hypoxia, metabolic stress, and immune checkpoint molecules drive NK cells into entirely different functional states. The review, authored by researchers from Northwest University and Xijing Hospital, Fourth Military Medical University in China, synthesizes emerging evidence on three major subsets: tumor-infiltrating natural killer (TiNK) cells, tissue-resident natural killer (TrNK) cells, and adaptive natural killer cells.
TiNK cells, recruited from blood, often become dysfunctional inside tumors. They downregulate activating receptors such as natural killer group 2 member D (NKG2D) and NK cell activating receptor 30 (NKp30), while upregulating inhibitory checkpoints including programmed cell death protein 1 (PD-1), T cell immunoreceptor with Ig and ITIM domains (TIGIT), and natural killer group 2 member A (NKG2A). Their metabolism also falters, with impaired glycolysis and mitochondrial respiration. In contrast, TrNK cells permanently reside in specific organs, express residency markers such as CD69 and CD103, and display functional plasticity that allows them to either suppress tumors or adopt pro-tumorigenic roles. Adaptive NK cells represent the most striking finding: they develop memory-like features in response to human cytomegalovirus (HCMV) infection, acquiring a natural killer group 2 member C-positive (NKG2C+) phenotype with enhanced antibody-dependent cellular cytotoxicity (ADCC), or through cytokine pre-activation with interleukin-12 (IL-12), IL-15, and IL-18, which reprograms them into 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 patients with acute myeloid leukemia and persistence exceeding three months after infusion. Emerging 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 including CRISPR-Cas9 gene editing, induced pluripotent stem cell-derived NK cells, and NK cell-derived extracellular vesicles are also advancing toward clinical translation.
"The old way of looking at NK cells as just two types doesn't work when you actually look inside tumors," the authors said. "What we're seeing is that the microenvironment is actively sculpting these cells into distinct versions of themselves — some are worn down, some stand their ground, and some actually become smarter and more potent over time. That complexity is both a challenge and an opportunity. 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."
The full review is available at https://doi.org/10.20892/j.issn.2095-3941.2025.0829. Additional information about the journal can be found through http://chuanlink-innovations.com.
