bims-nakice 2026-08-16 papers

Issue of 2026–08–16
five papers selected by
Santosh Phuyal, Oslo Universitetssykehus

JCI Insight. 2026 Aug 04. pii: e206701. [Epub ahead of print]

CXCR4 coordinates adhesion, migration, and development of human NK cells.

Shira E Eisman, Francesca E Grossberg, Batya S Koenigsberg, David H McDermott, Frédérique van den Haak, Luis A Pedroza, Everardo Hegewisch-Solloa, Philip M Murphy, Emily M Mace.

Natural killer (NK) cells undergo stepwise differentiation from multipotent progenitors within secondary lymphoid tissues. Despite the central importance of the tissue microenvironment in their development, little is known about cell-cell interactions that regulate human NK cell trafficking and maturation. Here, we identify the chemokine receptor CXCR4 and its ligand CXCL12 as regulators of stromal-NK cell interactions required for NK cell maturation. We demonstrate that CXCR4 is expressed throughout human NK cell development in peripheral blood and tonsil, and CXCL12 is enriched in stromal niches containing developing NK cells. Pharmacologic blockade or genetic disruption of CXCR4 resulted in diminished adhesion to integrin ligands, and high-resolution imaging demonstrated crosstalk between CXCR4 and integrins, providing a mechanistic basis for chemokine-dependent modulation of adhesion. Further, CXCR4 blockade resulted in altered contact-dependent motility on stromal cells and integrin ligands, with decreased stable stromal engagement and increased cell speed. Consistent with a requirement for these interactions, treatment with the CXCR4 antagonist plerixafor (AMD3100) impaired NK cell generation from CD34+ precursors. Analysis of NK cells from WHIM syndrome patients with CXCR4 gain-of-function mutations treated with plerixafor revealed similar defects in migration and adhesion, supporting the in-vivo relevance of CXCR4-dependent regulation of NK cell adhesion and motility.

Keywords: Cell biology; Cell migration/adhesion; Chemokines; Immunology; NK cells

DOI: https://doi.org/10.1172/jci.insight.206701

Sci Signal. 2026 Aug 11. 19(950): eady2865

LRP5-dependent transport of polyunsaturated fatty acids serves as an immune checkpoint for natural killer cells.

Yi Luan, Chuan Yang, Hongyue Zhou, Zhuo Chen, Ao Li, Peng Liu, Dianqing Wu, Wenwen Tang.

Polyunsaturated fatty acids (PUFAs) play a crucial role in tumor development by influencing not only tumor cells but also immune cells within the tumor microenvironment. Here, we explored the mechanisms by which PUFAs are transported and function within immune cells to regulate tumor growth. We found that PUFA transport through LDL receptor-related protein 5 (LRP5) into natural killer (NK) cells played an essential role in modulating the cells' antitumor function. LRP5 deficiency or expression of LRP5 lacking the LDLa domain enhanced the cytotoxicity and antitumor activity of NK cells both in vivo and in culture. However, wild-type NK cells cultured in the absence of PUFAs and NK cells from mice fed a PUFA-free diet also exhibited enhanced cytotoxicity, eliminating the functional difference between wild-type and NK cells expressing LDLa domain-deficient LRP5. Mechanistically, LRP5-mediated PUFA transport suppressed mTORC1 signaling and glycolysis in NK cells, a metabolic pathway essential for NK cell cytotoxicity. Thus, our study identified LRP5 as an immune checkpoint that restrains NK cell activity through PUFA transport-dependent suppression of mTORC1 signaling.

DOI: https://doi.org/10.1126/scisignal.ady2865

Trends Immunol. 2026 Aug 13. pii: S1471-4906(26)00186-9. [Epub ahead of print]

NK cells in breast cancer.

Andréa Massidda, Santiago Moragon-Terencio, Camille Baudesson de Chanville, Fabrice André, Eric Vivier, Emilie Narni-Mancinelli.

Natural killer (NK) cells are effectors of innate antitumor immunity, yet their therapeutic potential in solid tumors remains largely unrealized. Breast cancer exemplifies this paradox: NK cells are present in circulation and detectable within tumors, but their cytotoxic activity is limited. Recent advances in single-cell and spatial profiling reveal that NK-cell failure in breast cancer does not result from simple immune absence but from multilayered constraints imposed by the tumor ecosystem. Soluble mediators, metabolic pressures, stromal architecture, and suppressive immune networks reprogram NK-cell identity and uncouple activation from cytotoxicity. Understanding how these constraints shape NK-cell states reframes breast cancer as a model of innate immune dysfunction and highlights new opportunities to reestablish NK-cell function through immunotherapies.

DOI: https://doi.org/10.1016/j.it.2026.07.007

Front Cell Dev Biol. 2026 ;14 1916956

Beyond KIR and NKG2A blockade: reprogramming NK-cell immunity in solid tumors.

Claudia Pastorino, Michela Falco, Chiara Giordano, Najmeh Zarefeizabadi, Mariangela Rutigliani, Alessio Carbone, Matteo Clavarezza, Fulvia Ortolani, Luca Nanni, Mariella Della Chiesa, Simona Sivori, Simona Carlomagno.

Natural killer (NK) cells are uniquely equipped to eliminate transformed cells without prior antigen sensitization, yet their therapeutic potential in solid tumors remains only partially realized. At the center of this paradox lies a complex network of inhibitory pathways, dominated by killer cell immunoglobulin-like receptors (KIRs) and the CD94/NKG2A axis, which continuously calibrate NK-cell self-tolerance and effector competence. Tumors exploit these regulatory circuits through dynamic remodeling of HLA-I expression: while loss of classical HLA-I impairs CD8+ T-cell recognition, preservation or upregulation of non-classical HLA, particularly HLA-E, sustains inhibitory signaling and promotes immune escape. These mechanisms are further amplified by the tumor microenvironment (TME), where stromal barriers, hypoxia, metabolic stress, and immunosuppressive networks collectively restrict NK-cell infiltration, persistence, and cytotoxicity. Such multilayered suppression helps explain why therapeutic blockade of KIR or NKG2A alone has yielded only modest clinical benefit in most solid tumors, despite compelling biological rationale. Emerging evidence suggests that the KIR- and CD94/NKG2-centered network should be viewed not only as a therapeutic target but also as a framework for the next-generation of NK-cell-based immunotherapies. Future strategies will likely combine checkpoint modulation with donor- and patient-tailored NK-cell selection, engineered NK-cell products with enhanced metabolic resilience and reduced checkpoint sensitivity, and interventions aimed at remodeling the tumor niche to restore trafficking, persistence, and functional fitness. In this mini-review, we discuss how KIR- and CD94/NKG2-mediated signaling is shaped by the TME and examine emerging combinatorial and personalized approaches designed to unlock the full therapeutic potential of NK cells in solid tumors.

Keywords: KIR; NKG2A; immune checkpoints; natural killer cells; solid tumors

DOI: https://doi.org/10.3389/fcell.2026.1916956