[Elucidation of Natural Killer (NK) Cell Evasion Mechanisms in Colorectal Carcinogenesis Using Single-Cell RNA...

Natural killer (NK) cells play a critical role in antitumor immunity by rapidly eliminating stressed or transformed cells through recognition of reduced MHC classⅠexpression and upregulation of activating ligands such as MICA/B. However, accumulating evidence indicates that NK cells within the tumor microenvironment (TME) frequently exhibit functional exhaustion and impaired cytotoxicity. In this article, we review the molecular and spatial mechanisms underlying NK-cell dysfunction in colorectal tumorigenesis, with a particular focus on insights gained from single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics. Tumor-derived immunosuppressive factors, including transforming growth factor-β (TGF-β), prostaglandin E2, adenosine, and metabolic stressors such as hypoxia and nutrient deprivation, suppress NK-cell activation, cytokine production, and cytolytic function. These signals also promote the phenotypic conversion of NK cells into ILC1-like cells with reduced antitumor capacity. Spatial analyses of colorectal cancer tissues reveal a striking compartmentalization of NK-cell states. The activated NK cells expressing IFN-γ, GZMB, and PRF1 preferentially localize to tumor margins, whereas exhausted or ILC1-like NK cells predominate within tumor cores. Integrative analyses combining public scRNA-seq datasets with in-house spatial transcriptomic data demonstrate that NK cells are enriched in adenomatous lesions but are progressively excluded during the transition from adenoma to carcinoma, suggesting that NK cell evasion is an early event in colorectal cancer progression. Notably, NK cells that remain in close proximity to cancer cells retain enhanced cytotoxic and immune-activating signatures. Clinically, higher intratumoral NK-cell infiltration is significantly associated with improved overall survival, highlighting the importance of both NK-cell abundance and functional state. These findings underscore the therapeutic potential of targeting NK-cell exhaustion and reactivation. Strategies including NKG2A or TIGIT checkpoint blockade, inhibition of TGF-β signaling, metabolic reprogramming, and engineered NK-cell therapies such as CAR-NK or iPSC-derived NK cells represent promising approaches to restore NK-cell-mediated antitumor immunity in colorectal cancer.