ArticleThe Journal of clinical investigation2021
Dynamic single-cell RNA sequencing identifies immunotherapy persister cells following PD-1 blockade.
Article in The Journal of clinical investigation, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
52 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Disrupting Mechanisms that Regulate Genomic Repeat Elements to Combat Cancer and Drug Resistance.Frontiers in cell and developmental biology · 2022Pooled it
- Dissecting residual disease in spheroids reveals pan-cancer persistence signatures and a therapeutic window for oncolytic viruses.Molecular therapy. Oncology · 2026Article
- Therapy-Driven Molecular Evolution of Bladder Cancer: Roles of Cellular Plasticity and Tumor Microenvironment.International journal of molecular sciences · 2026Review
- Engineering Organ-on-a-Chip Systems for Cancer Immunotherapy: Strategies and Assay Integration.Bioengineering (Basel, Switzerland) · 2026Review
- Vascular STING activation facilitates NK cell anti-tumor immunity in small cell lung cancer.Cancer cell · 2026Article
- Drug-Tolerant Persister Cells and Tumor Dormancy in NSCLC: A New Frontier in Overcoming Therapeutic Resistance.Cancers · 2026Review
- Modeling Microbiome Modulation of Tumor Metabolic Networks to Predict Synergistic Therapies.bioRxiv : the preprint server for biology · 2026Article
- Reduced expression of BIRC2 and BIRC3 associated with longer survival in pediatric high-grade gliomas.Scientific reports · 2026Article
- Drug-tolerant persister cells in head and neck squamous cell carcinoma: Molecular mechanisms and therapeutic opportunities.Translational oncology · 2026Article
- Ectopic CD11c Drives SMAD3-Mediated Aberrant Antigen Presentation and Epithelial-Mesenchymal Transition in Esophageal Squamous Cell Carcinoma.Cancer communications (London, England) · 2026Article
- Artificial Intelligence-Enabled Multi-Omics for Predicting Immune Checkpoint Inhibitor Response and Resistance.Journal of multidisciplinary healthcare · 2026Review
- Drug-tolerant persister cells in lymphoid malignancies: from mechanisms to therapeutic opportunities.Frontiers in oncology · 2026Review
- Oligoclonal tumor-specific CD8 T-cell revival and IRE1α/XBP1-GDF15-mediated immunosuppressive niches determine neoadjuvant chemoimmunotherapy efficacy in cervical cancer.Journal for immunotherapy of cancer · 2025Article
- BLID is a drug-responsive target of FOXO3a and multi-omics analysis reveals survival mechanisms and therapeutic vulnerabilities in BLID-deficient breast cancer cells.Oncology letters · 2025Article
- Cancer-on-a-chip for precision cancer medicine.Lab on a chip · 2025Review
- Patient-derived organotypic tumor spheroids, tumoroids, and organoids: advancing immunotherapy using state-of-the-art 3D tumor model systems.Lab on a chip · 2025Review
- Drug-induced tolerant persisters in tumor: mechanism, vulnerability and perspective implication for clinical treatment.Molecular cancer · 2025Review
- BIRC2 blockade facilitates immunotherapy of hepatocellular carcinoma.Molecular cancer · 2025Article
- Cancer stem cells and niches: challenges in immunotherapy resistance.Molecular cancer · 2025Review
- Resistance mechanisms to immune checkpoint inhibitors: updated insights.Molecular cancer · 2025Review
Corrections and comments
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Authors and funding
28 authors.
Funding
Abstract
Resistance to oncogene-targeted therapies involves discrete drug-tolerant persister cells, originally discovered through in vitro assays. Whether a similar phenomenon limits efficacy of programmed cell death 1 (PD-1) blockade is poorly understood. Here, we performed dynamic single-cell RNA-Seq of murine organotypic tumor spheroids undergoing PD-1 blockade, identifying a discrete subpopulation of immunotherapy persister cells (IPCs) that resisted CD8+ T cell-mediated killing. These cells expressed Snai1 and stem cell antigen 1 (Sca-1) and exhibited hybrid epithelial-mesenchymal features characteristic of a stem cell-like state. IPCs were expanded by IL-6 but were vulnerable to TNF-α-induced cytotoxicity, relying on baculoviral IAP repeat-containing protein 2 (Birc2) and Birc3 as survival factors. Combining PD-1 blockade with Birc2/3 antagonism in mice reduced IPCs and enhanced tumor cell killing in vivo, resulting in durable responsiveness that matched TNF cytotoxicity thresholds in vitro. Together, these data demonstrate the power of high-resolution functional ex vivo profiling to uncover fundamental mechanisms of immune escape from durable anti-PD-1 responses, while identifying IPCs as a cancer cell subpopulation targetable by specific therapeutic combinations.
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