Natural killer (NK) cells are frontline immune defenders against cancer, but their behavior inside tumors is far more complex than previously understood. A comprehensive review now shows that the tumor microenvironment does not simply suppress these cells — it actively reshapes them into distinct functional subsets with specialized roles, ranging from exhausted fighters to potent memory-like killers. The findings challenge the traditional binary classification of NK cells and offer a new framework for designing more precise cancer immunotherapies.
For decades, natural killer (NK) cells have been classified into two main groups based on surface markers: one specialized for cytokine production and the other for direct killing. But this system, derived primarily from blood studies, fails to capture how these cells behave once they enter solid tumors. Within the tumor microenvironment, factors such as hypoxia, metabolic stress, and immune checkpoint molecules drive NK cells into entirely different functional states — some become exhausted, others adopt tissue-resident roles, and still others develop memory-like properties. Based on these challenges, there is an urgent need to systematically characterize these specialized subsets and understand the molecular rules governing their formation and function.
A team of researchers from Northwest University and Xijing Hospital, Fourth Military Medical University in China has published a comprehensive review in Cancer Biology & Medicine (April 2026) that maps the landscape of tumor-infiltrating NK cell subsets. 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 — and outlines how each subset responds differently to microenvironmental signals, offering distinct opportunities for therapeutic intervention.
The review identifies three functionally distinct subsets shaped by the microenvironment. 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. TrNK cells, in contrast, 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. Adaptive NK cells represent the most striking finding — they develop memory-like features either 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 review further details how immune checkpoint expression, metabolic reprogramming, cytokine signaling networks, and intercellular interactions differentially regulate each subset, revealing a dynamic and interconnected network rather than isolated populations.
"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 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 and favorable outcomes across multiple cancer types. Adaptive NK cells — particularly cytokine-induced memory-like natural killer (CIML-NK) cells — have already 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. The review also highlights next-generation platforms including CRISPR-Cas9 gene editing, induced pluripotent stem cell-derived NK cells, and NK cell-derived extracellular vesicles, all advancing toward clinical translation.
The full review is available at https://doi.org/10.20892/j.issn.2095-3941.2025.0829. For more information about the journal, visit http://chuanlink-innovations.com.
