Pluripotent stem cell-derived NK progenitor cell therapy prevents tumour occurrence and eradicates minimal residual disease

Wang, Z.; Lin, Y.; Huang, D.; Zhang, L.; Xia, C.; Weng, Q.; Liu, Y.; Wang, T.; Zhang, M.; Wu, J.; Qi, H.; Liu, L.; Shen, Y.; Chen, Y.; Zhu, Y.; Hu, F.; Wang, J.

doi:10.1101/2025.01.07.631650

bioRxiv · 10.1101/2025.01.07.631650

Pluripotent stem cell-derived NK progenitor cell therapy prevents tumour occurrence and eradicates minimal residual disease

Wang, Z.·Lin, Y.·Huang, D.·Zhang, L.·Xia, C.·Weng, Q.·Liu, Y.·Wang, T.·Zhang, M.·Wu, J.·Qi, H.·Liu, L.·Shen, Y.·Chen, Y.·Zhu, Y.·Hu, F.·Wang, J.

View original source ↗Export metadata ↓

Abstract

The lack of persistence and short-term efficacy presents a major challenge for CAR-NK cell therapy. Here, we addressed this issue by developing pluripotent stem cell-derived NK lineage-committed progenitor (iNKP) cell therapy. For the first time, we generated abundant iNKP cells via an organoid culture system. The iNKP cells, engineered to express CXCR4 and chimeric antigen receptors (CAR), efficiently migrated to the bone marrow and generated CAR-iNK cells persisting in peripheral blood (PB) for over 80 days. Notably, CAR-iNKP cell therapy durably protected animals from tumour occurrence. Furthermore, a single low-dose infusion of CAR-iNKP cells following conventional chemotherapy eradicated minimal residual disease (MRD), leading to long-term complete remission. Our findings present a novel strategy to overcome the limitations of traditional CAR-NK cell therapy and offer dural breakthroughs for the prevention of tumour occurrence and relapse.

Explore related subjects

cancer biology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Wang, Z., Lin, Y., Huang, D., Zhang, L., Xia, C., Weng, Q., Liu, Y., Wang, T., Zhang, M., Wu, J., Qi, H., Liu, L., Shen, Y., Chen, Y., Zhu, Y., Hu, F., Wang, J.. 2025-01-08. Pluripotent stem cell-derived NK progenitor cell therapy prevents tumour occurrence and eradicates minimal residual disease. https://doi.org/10.1101/2025.01.07.631650

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

An expanded, phenotypically distinct tumor cell subset with low HPV mRNA increases recurrence risk

Human papillomavirus-related (HPV+) cancers harbor a subset of tumor cells expressing certain senescence-related transcripts and reduced levels of HPV mRNAs. We aimed to define this HPV-low population's biologic traits and clinical significance via integrated analysis of recurrence-prone human HPV+ oropharyngeal cancers (OPCs) and patient-derived xenografts (PDXs) of variable therapy sensitivity. Single-cell mRNA sequencing of PDXs and human tumors detected gene expression profiles in HPV-low cells indicating lack of senescence or terminal differentiation and intact tumorigenic capacity. HPV-low cells in cisplatin-refractory PDXs and particular human OPCs differentially upregulated multiple pathways linked to aggressive tumor biology, including RAS signaling, IL-6 signaling, and EMT. Predicted loss of cell-cell interactions among HPV-low cells reflected reduced epithelial identity, further supporting their more aggressive biology. Accordingly, the size of the pre-treatment HPV-low fraction had strong, independent association with recurrence risk. Genetic subclones within OPCs varied widely in content of HPV-low cells, which were enriched in particular lineages. Our findings uncover novel pro-tumor functions of HPV-low cells and support a central role for them in therapy resistance as well as potential utility as a clinical biomarker. Further elucidating mechanisms of cooperativity and plasticity between HPV-low and high states holds promise to reveal targets in treatment-refractory HPV+ malignancies.

cancer biology↗

bioRxiv2026

Discovery of molecular glues for modulating MHC presentation of cancer neoantigens

Antigen presentation by MHC class I molecules is essential for cancer immunosurveillance, but many cancer-specific antigens fail to form complexes with Class I MHC and are poorly presented on the cell surface. In this study, we present a chemical strategy to overcome this limitation by identifying peptide MHC glues (PMGs) that promote the formation of peptide-MHC complexes with otherwise unpresentable cancer antigens. Crystal structures of these complexes show that our compounds stabilize antigen-MHC binding by making simultaneous interactions with the MHC protein and the antigen peptides. These findings reveal a new approach for chemically rewiring Class I MHC antigen presentation and accessing rare cancer antigens for therapeutic targeting.

cancer biology↗

bioRxiv2026

mRNA-LNP vaccination induces microenvironment remodeling and generation of tissue-resident memory T cells in glioblastoma

Glioblastoma remains highly refractory to immunotherapy, in part because of a profoundly immunosuppressive tumour microenvironment that limits effective T-cell responses. Although mRNA vaccines can induce anti-tumour immunity, how they reshape the glioblastoma immune ecosystem to support durable tumour control is not well understood. Here we use an immunocompetent EGFRvIII-driven syngeneic glioblastoma model and antigen-specific mRNA lipid nanoparticle (mRNA-LNP) vaccination to define the cellular and spatial mechanisms underlying therapeutic response. In our model, vaccination induced durable EGFRvIII-specific humoral and cellular immunity, resulting in complete tumour eradication and long-term protection against intracranial rechallenge. Integrative analyses incorporating flow cytometry, tumour interstitial fluid profiling, multiplex immunostaining, spatial transcriptomics and ligand-receptor modelling demonstrated extensive remodelling of the tumour microenvironment following vaccination. Early tumour control was associated with expansion of pro-inflammatory and antigen-presenting myeloid populations, increased cytotoxic CD8 T-cell infiltration and activation, enhanced interferon-responsive signalling, and the formation of immune-supportive spatial niches enriched for antigen presentation and chemokine-mediated cellular communication. Vaccination promoted inflammatory chemokine relay networks centred on the CXCL16-CXCR6 axis, a pathway linked to tissue residency programming in the central nervous system. Functional depletion studies identified CD4 and CD8 T cells as essential mediators of therapeutic efficacy, while durable protection was maintained by tumour-specific brain-resident memory CD8 T cells that persisted despite peripheral lymphocyte depletion. Together, these findings identify T-cell-driven microenvironmental remodelling as a critical mechanism linking mRNA vaccination to the establishment of long-term brain-resident anti-tumour immunity in glioblastoma.

cancer biology↗