ArticleCancer communications (London, England)2024
Targeting autophagy overcomes cancer-intrinsic resistance to CAR-T immunotherapy in B-cell malignancies.
Article in Cancer communications (London, England), 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 20 citations in OpenAlex.
- B Cells and Tumor Immunometabolism: Emerging Insights into Immune Regulation and Therapeutic Resistance.Antibodies (Basel, Switzerland) · 2026Review
- Metabolism, autophagy, and cell death: The triangular axis in tumor survival and therapeutic resistance.Redox biology · 2026Review
- High-Content CRISPR Screening: Methods and Applications.MedComm · 2026Review
- Reprogramming Autophagy to Strengthen Antitumour Immunity: Advances in Immunotherapeutic Strategies.Immunology · 2026Review
- Challenges and advances in CAR-T cell therapy for B-ALL.Biomarker research · 2026Review
- Targeting CD74 may mitigate immune-escape features and enhance BCMA CAR-T activity in preclinical models of relapsed/refractory multiple myeloma.Journal for immunotherapy of cancer · 2026Article
- Autophagy Modulates Immunogenic Cell Death in Cancer.Cancers · 2026Review
- Editorial: Unlocking autophagy's full potential: embracing a multidimensional approach for targeted cancer treatment.Frontiers in pharmacology · 2026Article
- Translational potential of γδ T cells in hematologic diseases: from immunobiology to therapeutic innovation.Frontiers in immunology · 2026Review
- Overcoming Resistance and Relapse in CAR-T and CAR-NK Cell Therapies: From Bench to Bedside.Research (Washington, D.C.) · 2026Article
- Targeting autophagy in dysfunctional tumor vasculature.iScience · 2025Review
- Phage therapy and the microbiome in hematologic malignancies: opportunities, mechanisms, and early evidence.Journal of cancer research and clinical oncology · 2025Review
- Ultrasound Visualization of Spatiotemporal Autophagy-Regulated Nanodroplets for Amplifying ICB in Melanoma via Remodeling Tumor Inflammatory Microenvironment.ACS applied materials & interfaces · 2025Article
- Advances in cancer immunotherapy: historical perspectives, current developments, and future directions.Molecular cancer · 2025Review
- From Multi-Omics to Visualization and Beyond: Bridging Micro and Macro Insights in CAR-T Cell Therapy.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Review
- Targeting secretory autophagy in solid cancers: mechanisms, immune regulation and clinical insights.Experimental hematology & oncology · 2025Review
- MYC Overexpression Enhances Sensitivity to MEK Inhibition in Head and Neck Squamous Cell Carcinoma.International journal of molecular sciences · 2025Article
- Igniting Cold Tumors: Multi-Omics-Driven Strategies to Overcome Immune Evasion and Restore Immune Surveillance.Oncology research · 2025Review
- VPS37A Activates the Autophagy-Lysosomal Pathway for TNFR1 Degradation and Induces NF-Oncology research · 2025Article
- A mini-review-cancer energy reprogramming on drug resistance and immune response.Translational oncology · 2024Review
Corrections and comments
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Authors and funding
21 authors at 2 institutions in 2 countries.
Funding
Abstract
backgroundChimeric antigen receptor T (CAR-T) therapy has substantially revolutionized the clinical outcomes of patients with hematologic malignancies, but the cancer-intrinsic mechanisms underlying resistance to CAR-T cells remain yet to be fully understood. This study aims to explore the molecular determinants of cancer cell sensitivity to CAR-T cell-mediated killing and to provide a better understanding of the underlying mechanisms and potential modulation to improve clinical efficacy.
methodsThe human whole-genome CRISPR/Cas9-based knockout screening was conducted to identify key genes that enable cancer cells to evade CD19 CAR-T-cell-mediated killing. The in vitro cytotoxicity assays and evaluation of tumor tissue and bone marrow specimens were further conducted to confirm the role of the key genes in cancer cell susceptibility to CAR-T cells. In addition, the specific mechanisms influencing CAR-T cell-mediated cancer clearance were elucidated in mouse and cellular models.
resultsThe CRISPR/Cas9-based knockout screening showed that the enrichment of autophagy-related genes (ATG3, BECN1, and RB1CC1) provided protection of cancer cells from CD19 CAR-T cell-mediated cytotoxicity. These findings were further validated by in vitro cytotoxicity assays in cells with genetic and pharmacological inhibition of autophagy. Notably, higher expression of the three autophagy-related proteins in tumor samples was correlated with poorer responsiveness and worse survival in patients with relapsed/refractory B-cell lymphoma after CD19 CAR-T therapy. Bulk RNA sequencing analysis of bone marrow samples from B-cell leukemia patients also suggested the clinical relevance of autophagy to the therapeutic response and relapse after CD19 CAR-T cell therapy. Pharmacological inhibition of autophagy and knockout of RB1CC1 could dramatically sensitize tumor cells to CD19 CAR-T cell-mediated killing in mouse models of both B-cell leukemia and lymphoma. Moreover, our study revealed that cancer-intrinsic autophagy mediates evasion of CAR-T cells via the TNF-α-TNFR1 axis-mediated apoptosis and STAT1/IRF1-induced chemokine signaling activation.
conclusionsThese findings confirm that autophagy signaling in B-cell malignancies is essential for the effective cytotoxic function of CAR-T cells and thereby pave the way for the development of autophagy-targeting strategies to improve the clinical efficacy of CAR-T cell immunotherapy.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.