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IPSC-Derived CAR-NK Extracellular Vesicles Remodel Macrophage Immunity and Enhance Tumor Eradication

ABSTRACT: Chimeric antigen receptor (CAR) cell therapy has revolutionized the treatment of hematological malignancies; however, its efficacy in solid tumors remains limited due to dense stromal barriers and the immunosuppressive tumor microenvironment (TME), which hinder immune cell infiltration and persistence. To overcome these challenges, we propose an innovative strategy utilizing induced pluripotent stem cell (iPSC)-derived CAR-NK extracellular vesicles (CAR-iNEV), engineered from iPSC-differentiated NK cells. Unlike conventional CAR-NK cell therapies that rely on immortalized NK92 cell lines, our approach leverages iPSC-derived NK cells, reducing tumorigenic risk and enhancing CAR transduction efficiency. Additionally, we incorporate nanobody-based CAR constructs in place of traditional single-chain variable fragments (scFv), significantly improving CAR stability and expression efficiency. Beyond direct cytotoxicity, CAR-iNEV offers superior therapeutic advantages, including reduced systemic toxicity and enhanced drug delivery capabilities compared to CAR-iNK cells. In vivo studies demonstrate that CAR-iNEV exhibits exceptional safety and potent antitumor activity across multiple solid tumor xenograft and patient-derived xenograft (PDX) models in humanized mice. Mechanistically, CAR-iNEV not only directly eliminates tumor cells but also reprograms the TME by activating macrophage-derived nitric oxide synthase (NOS2), amplifying host antitumor immunity. These findings establish CAR-iNEV as a promising platform for solid tumor immunotherapy, particularly in relapsed and metastatic settings, providing a novel and effective strategy that bridges direct tumor targeting with immune microenvironment remodeling. This study lays the foundation for future clinical translation, advancing the next generation of cell-free CAR-based immunotherapies.

ORGANISM(S): Mus musculus

PROVIDER: GSE293929 | GEO | 2025/11/26

REPOSITORIES: GEO

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Project description:A significant challenge for chimeric antigen receptor (CAR) T cell therapy against glioblastoma (GBM) is its immunosuppressive tumor microenvironment (TME), which is densely populated and supported by protumoral glioma-associated microglia and macrophages (GAMs). Targeting CD47, a don't-eat-me signal overexpressed by tumor cells, disrupts the CD47-SIRPalpha axis and induces GAM phagocytic function. However, antibody-mediated CD47 blockade monotherapy is associated with toxicity and low bioavailability in solid tumors. To overcome these limitations, we combined local CAR T cell therapy with paracrine GAM modulation to effectively eliminate GBM. To this end, we engineered a new CAR T cell against epidermal growth factor receptor variant III (EGFRvIII) that constitutively secretes a signal regulatory protein gamma (SIRPgamma)-related protein (SGRP) with high affinity to CD47. Anti-EGFRvIII-SGRP CAR T cells eliminated EGFRvIII+ GBM in a dose-dependent manner in vitro and eradicated orthotopically xenografted EGFRvIII-mosaic GBM by locoregional application in vivo. This resulted in significant tumor-free long-term survival, followed by partial tumor control upon tumor re-challenge. Combining anti-CD47 antibodies with anti-EGFRvIII CAR T cells failed to achieve a similar therapeutic effect, underscoring the importance of sustained paracrine GAM modulation. Multidimensional brain immunofluorescence microscopy and in-depth spectral flow cytometry on GBM-xenografted brains showed that anti-EGFRvIII-SGRP CAR T cells accelerated GBM clearance, increased CD68+ cell trafficking to tumor scar sites and promoted GAM-mediated tumor cell uptake. In a peripheral lymphoma mouse xenograft model, anti-CD19-SGRP CAR T cells had superior efficacy to conventional anti-CD19 CAR T cells. Validation on human GBM explants revealed that anti-EGFRvIII-SGRP CAR T cells had a similar tumor-killing capacity to anti-EGFRvIII CAR monotherapy but showed a slight improvement in the maintenance of tumor-infiltrated CD14+ cells. Thus, local anti-EGFRvIII-SGRP CAR T cell therapy combines the potent antitumor effect of engineered T cells with the modulation of the surrounding innate immune TME. This results in the additive elimination of bystander EGFRvIII- tumor cells in a manner that overcomes the main mechanisms of CAR T cell therapy resistance, including tumor innate immune suppression and antigen escape.

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IPSC-Derived CAR-NK Extracellular Vesicles Remodel Macrophage Immunity and Enhance Tumor Eradication

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