ArticleSignal transduction and targeted therapy2025
Neoleukin-2/15-armored CAR-NK cells sustain superior therapeutic efficacy in solid tumors via c-Myc/NRF1 activation.
Article in Signal transduction and targeted therapy, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 40 papers.
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Who cites it
40 citing papers in PubMed.
- Advances in natural killer cell immunotherapy for hematologic malignancies.Cancer biology & therapy · 2026Review
- Natural killer cells in ovarian cancer therapy: mechanisms, evasion, and therapeutic innovations.Inflammopharmacology · 2026Review
- Arming oncolytic Coxsackievirus B3 with Neoleukin-2/15 enhances growth inhibition of colorectal carcinomas and induces T cell activation.Molecular therapy. Oncology · 2026Article
- Cell-Type-Tailored Hydrogels for Adoptive Cell Therapy in Cancer.Gels (Basel, Switzerland) · 2026Review
- Regulatory T cells sabotage anti-tumor γδ T cells by creating IL-2-deficient environments.The Journal of experimental medicine · 2026Article
- Review
- Next-generation CAR-NK cell therapy: engineering strategies, translational challenges, and future perspectives in cancer immunotherapy.Cancer cell international · 2026Review
- Efficient, fratricide free non-viral engineering of CD70-targeted CAR NK cells for hematologic and solid tumor immunotherapy.Molecular therapy. Advances · 2026Article
- Bioenergetic-active hybrid nanovesicles empower tumor associated macrophages phagocytosis for cancer immunotherapy.Materials today. Bio · 2026Article
- CAR-engineering of innate and innate-like immune cells: a new horizon in adoptive cell therapy for solid tumors.Journal for immunotherapy of cancer · 2026Review
- Constitutive RLI Armoring Enhances CAR-NK Cell Effector Functions but Causes Lethal Toxicity In Vivo.International journal of molecular sciences · 2026Article
- SMAD7 drives natural killer cell antitumor activity through canonical TGF-β blockade and non-canonical transcriptional activation of STAT5A.Journal for immunotherapy of cancer · 2026Article
- Immune Exhaustion in Chronic Infection and Cancer: Signaling Pathways and Therapeutic Interventions.MedComm · 2026Review
- Engineering Immune Cell to Counteract Aging and Aging-Associated Diseases.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Review
- Targeting metabolic reprogramming to enhance adoptive immunotherapy: emerging mechanisms and translational perspectives.Journal of translational medicine · 2026Review
- CAR-engineered cell therapies: current understandings and future perspectives.Molecular biomedicine · 2026Review
- Integrative single-cell transcriptomics and proteomics reveal an immunometabolic framework for MSC-exosome-mediated remodeling of expanded NK cells.GigaScience · 2026Article
- Enhancing CAR-NK persistence to unlock its full therapeutic potentials.Frontiers in immunology · 2026Review
- Dual-module aCAR-iCAR NK cells for solid tumors: cascade resistance mechanisms, AI-driven engineering, and precision stratification.Frontiers in immunology · 2026Review
- Cell-drug conjugates: a novel drug delivery system for cancer therapy.Theranostics · 2026Review
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Authors and funding
7 authors.
Funding
Abstract
Adoptive transfer of chimeric antigen receptor (CAR)-modified natural killer (NK) cells represents a transformative approach that has significantly advanced clinical outcomes in patients with malignant hematological conditions. However, the efficacy of CAR-NK cells in treating solid tumors is limited by their exhaustion, impaired infiltration and poor persistence in the immunosuppressive tumor microenvironment (TME). As NK cell functional states are associated with IL-2 cascade, we engineered mesothelin-specific CAR-NK cells that secrete neoleukin-2/15 (Neo-2/15), an IL-2Rβγ agonist, to resist immunosuppressive polarization within TME. The adoptively transferred Neo-2/15-armored CAR-NK cells exhibited enhanced cytotoxicity, less exhaustion and longer persistence within TME, thereby having superior antitumor activity against pancreatic cancer and ovarian cancer. Mechanistically, Neo-2/15 provided sustained and enhanced downstream IL-2 receptor signaling, which promotes the expression of c-Myc and nuclear respiratory factor 1 (NRF1) in CAR-NK cells. This upregulation was crucial for maintaining mitochondrial adaptability and metabolic resilience, ultimately leading to increased cytotoxicity and pronounced persistence of CAR-NK cells within the TME. The resistance against TME immunosuppressive polarization necessitated the upregulation of NRF1, which is essential to the augmentative effects elicited by Neo-2/15. Overexpression of NRF1 significantly bolsters the antitumor efficacy of CAR-NK cells both in vitro and in vivo, with increased ATP production. Collectively, Neo-2/15-expressing CAR-NK cells exerts superior antitumor effects by exhaustion-resistance and longer survival in solid tumors.
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