NKG2D (killer cell lectin like receptor K1)

Therapeutic strategies including activation of NK cells via chemotherapeutics (bortezomib, decitabine), blockade of inhibitory receptors (NKG2A, CD161), and combinatorial approaches with immune checkpoint inhibitors are under active investigation. Notably, chimeric antigen receptor (CAR)-engineered NK cells targeting EGFR, HER2, GD2, and CD133 show promise in preclinical glioma models due to their enhanced specificity and reduced toxicity compared to CAR-T cells. This review summarizes the multifaceted roles of NK cells in glioma immunity and highlights novel immunotherapeutic strategies to restore NK cell function and improve clinical outcomes.

In contrast, in patient-derived xenograft (PDX) models, eNK cells demonstrated modest tumor growth inhibition (28% reduction) as monotherapy and significantly enhanced efficacy (53% inhibition) in combination with cetuximab via antibody-dependent cellular cytotoxicity. In treated PDX tumors, human CD45-positive cells were detected within the tumor parenchyma, supporting intratumoral presence of administered human cells.These findings support the potential contribution of the five-gene modifications in enhancing tumor homing, persistence, and cytotoxicity in solid tumor treatment. This study underscores the potential of eNK cells as a novel, "off-the-shelf" allogeneic therapy for refractory solid tumors, including lung cancer.

These findings demonstrate profound intrafamilial heterogeneity in XMEN disease and suggest a model in which modifier-sensitive factors influence organ-specific disease expression. The observation of lymphoma-associated thrombotic microangiopathy and the proposed descriptive neurological classification provide a conceptual framework that may help guide tailored, multidisciplinary surveillance beyond the primary genetic defect.

These data map the microenvironmental and transcriptional changes associated with rapid CAR-T cell dysfunction in GB and identify candidate pathways and regulators that may be leveraged to engineer more durable cellular therapies.

Clinical glioma specimens showed that the USP14 overexpression was correlated with PARP1 and dysfunctional CD8+ T cell infiltration. These results demonstrate that USP14 inhibition restores MIC-A/B-mediated CD8+ T cell activation, reverses immune exhaustion, and represents a promising strategy to enhance glioma immunotherapy.

However, the NKG2D ligands induced by PARP inhibitor was reduced in STING or IRF3-knockdown LSCs, indicating that STING and IRF3 were necessary for the regulation of NGK2D ligands in LSCs upon the DNA damage response. These data indicated that the DNA damage response-mediated cGAS/STING/TBK1/IRF3 signalling pathway played an essential role in modulating NKG2D ligands expression in LSCs.

Combination strategies incorporating chemotherapy and immunotherapy demonstrated promising synergistic potential, suggesting that multimodal approaches may enhance therapeutic efficacy while potentially mitigating resistance mechanisms. The convergence of innovative preclinical developments with increasingly supportive regulatory frameworks portends transformative advances in the field, positioning CAR-based cell therapy as an emerging cornerstone modality in the therapeutic armamentarium against GIM.

Our study establishes RRM2-driven trafficking as a novel and targetable mechanism of antigen escape in CAR-T therapy. By repurposing osalmid to restore MICA/B surface presentation, we provide a clinically translatable strategy that specifically potentiates NKG2D CAR-T cell efficacy in multiple myeloma and could potentially enhance the efficacy of CAR-T across diverse antigens. This work highlights the therapeutic potential of modulating intracellular trafficking to overcome resistance in cellular immunotherapy.

Meanwhile, due to the innate cytotoxicity and lack of alloreactivity, MAIT cells are attractive candidates for cellular immunotherapy. This review summarizes the functional dichotomy of MAIT cells in cancers and outlines strategies to harness their anti-tumor properties.

The importance of the NKG2A: HLA-E immune checkpoint axis was established using both HLA-E knockout EBV+ LCL and antibody blockade of NKG2A which demonstrated enhanced NK-mediated cytotoxicity in the absence of NKG2A-HLA-E interactions. Taken together, our results support that NKG2A+ NK cells are educated and functionally cytotoxic against EBV-infected B cells and suggest therapeutics targeting the NKG2A: HLA-E immune checkpoint axis would be a good option for EBV-associated malignancies.

Intranasal administration of the SIS3-VAP-DAC nanoemulsion effectively reduced pulmonary tumor burden in human osteosarcoma xenograft mouse models with no observable clinical toxicity. This study establishes a novel inhalable nanoemulsion platform that significantly restores NK-cell functionality against pulmonary metastatic osteosarcoma.