ArticleCommunications biology2021
Tumor-derived NKG2D ligand sMIC reprograms NK cells to an inflammatory phenotype through CBM signalosome activation.
Article in Communications biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed, 18 citations in OpenAlex.
- Therapeutic targeting of MALT1 in oncology: Mechanism, inhibitor development, and clinical prospects.Journal of cell communication and signaling · 2026Review
- Engineered CAR-T extracellular vesicles loaded with miR-17-5p inhibitor suppress hepatocellular carcinoma progression.Frontiers in immunology · 2026Article
- The Role of MICA/B Molecules and the NKG2D Receptor in the Interaction Between NK-92 Cells and JEG-3 Cells.International journal of molecular sciences · 2025Article
- Unleashing NK cells for cancer immunotherapy in lung cancer: biologic challenges and clinical advances.Journal of experimental & clinical cancer research : CR · 2025Review
- The Human Soluble NKG2D Ligand Differentially Impacts Tumorigenicity and Progression in Temporal and Model-Dependent Modes.Biomedicines · 2024Article
- Natural killer cells drive 4-1BBL positive uveal melanoma towards EMT and metastatic disease.Journal of experimental & clinical cancer research : CR · 2024Article
- In-depth analysis of the interplay between oncogenic mutations and NK cell-mediated cancer surveillance in solid tumors.Oncoimmunology · 2024Review
- Functional crosstalk and regulation of natural killer cells in tumor microenvironment: Significance and potential therapeutic strategies.Genes & diseases · 2023Review
- The Advantages and Challenges of Anticancer Dendritic Cell Vaccines and NK Cells in Adoptive Cell Immunotherapy.Vaccines · 2021Review
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 1 country.
Funding
Abstract
Natural Killer (NK) cell dysfunction is associated with poorer clinical outcome in cancer patients. What regulates NK cell dysfunction in tumor microenvironment is not well understood. Here, we demonstrate that the human tumor-derived NKG2D ligand soluble MIC (sMIC) reprograms NK cell to secrete pro-tumorigenic cytokines with diminished cytotoxicity and polyfunctional potential. Antibody clearing sMIC restores NK cell to a normal cytotoxic effector functional state. We discovered that sMIC selectively activates the CBM-signalosome inflammatory pathways in NK cells. Conversely, tumor cell membrane-bound MIC (mMIC) stimulates NK cell cytotoxicity through activating PLC2γ2/SLP-76/Vav1 pathway. Ultimately, antibody targeting sMIC effectuated the in vivo anti-tumor effect of adoptively transferred NK cells. Our findings uncover an unrecognized mechanism that could instruct NK cell to a dysfunctional state in response to cues in the tumor microenvironment. Our findings provide a rationale for co-targeting sMIC to enhance the efficacy of the ongoing NK cell-based cancer immunotherapy.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.