Regulatory Networks of Non-Coding RNAs Modulating Natural Killer Cell Antitumor Immunity in the Tumor Microenvironment

The intricate intercellular communication within the tumor microenvironment (TME) critically drives cancer progression and therapeutic resistance. Natural killer (NK) cells are potent sentinels of the innate immune system, but their antitumor functions are often severely compromised by the TME’s immunosuppressive networks. Moving beyond protein-coding genes, non-coding RNAs (ncRNAs)—with microRNAs (miRNAs) playing a foundational role alongside long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs)—have emerged as vital components of the regulatory networks influencing immune responses. Rather than dictating immune cell fate, these diverse transcriptomic classes form complex networks that modulate NK cell functional states and TME immunosuppression. This review systematically elucidates the molecular mechanisms by which these ncRNA networks influence NK cell biology in the TME. We dissect three core regulatory axes driven by extracellular vesicle (EV)-mediated communication, competitive endogenous RNA crosstalk, and epigenetic remodeling: the extrinsic suppression of NK cells by EV-derived and secreted ncRNAs from TME-resident cells, the reciprocal modulation of TME components by NK cell-derived ncRNAs, and the intrinsic regulation of NK cell functions by endogenous ncRNAs. Furthermore, we critically assess the clinical translational potential of targeting these networks. We highlight specific ncRNAs as non-invasive prognostic biomarkers and summarize targeted therapeutic interventions using antisense oligonucleotides, small interfering RNAs, and nano-delivery systems. Modulating these core ncRNA nodes to mitigate TME immunosuppression offers a novel paradigm for precision oncology, holding substantial promise for enhancing immune checkpoint blockade and NK cell-directed immunotherapies.