ArticlePLoS biology2020
IRE1α regulates macrophage polarization, PD-L1 expression, and tumor survival.
Article in PLoS biology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers.
What it found
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The trial behind it
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Who cites it
64 citing papers in PubMed, 117 citations in OpenAlex.
- Targeting myeloid cell plasticity and metabolic reprogramming to alleviate T cell dysfunction and exhaustion-associated states and enhance immune checkpoint blockade therapy.Biomarker research · 2026Review
- XBP1 signaling from tumor metabolic stress to myeloid driven immunotherapy resistance (Review).International journal of molecular medicine · 2026Review
- Endoplasmic reticulum stress promotes colorectal cancer proliferation by regulating autophagy via XBP1s.Translational cancer research · 2026Article
- The mannosyltransferase DPM1 regulates the activity of ER-stress sensor IRE1 in colorectal cancer.Nature communications · 2026Article
- Multifunctional nanotherapeutics for targeted modulation of endoplasmic reticulum stress to potentiate cancer therapy.Asian journal of pharmaceutical sciences · 2026Review
- Endoplasmic reticulum stress in antitumor immunity and immunotherapy resistance: mechanisms and therapeutic implications.Molecular cancer · 2026Review
- Endoplasmic reticulum stress in autoimmune skin diseases: immune activation, cutaneous cell damage, and therapeutic advances.Frontiers in immunology · 2026Review
- The IRE1α Pathway Links Endoplasmic Reticulum Stress to Atherosclerosis-Related Inflammation and Lipid Accumulation.Mediators of inflammation · 2026Article
- Targeting the unfolded protein response for cancer therapy: mitigating tumor adaptation and immune suppression.Biomarker research · 2025Review
- PRKCSH deficiency promotes an anti-tumor immune microenvironment via UPR activation and M1 macrophage polarization.Cancer cell international · 2025Article
- The Unfolded Protein Response-Novel Mechanisms, Challenges, and Key Considerations for Therapeutic Intervention.Cancers · 2025Review
- Navigating the landscape of protein folding and proteostasis: from molecular chaperones to therapeutic innovations.Signal transduction and targeted therapy · 2025Review
- Targeting proteostasis for cancer therapy: current advances, challenges, and future perspectives.Molecular cancer · 2025Review
- Small protein ERSP encoded by LINC02870 promotes triple negative breast cancer progression via IRE1α/XBP1s activation.Cell death and differentiation · 2025Article
- Review
- Endoplasmic Reticulum Stress: Triggers Microenvironmental Regulation and Drives Tumor Evolution.Cancer medicine · 2025Review
- Noncanonical UPR factor CREB3L2 drives immune evasion of triple-negative breast cancer through Hedgehog pathway modulation in T cells.Science advances · 2025Article
- MicroRNA: role in macrophage polarisation and colorectal cancer pathogenesis.Frontiers in cell and developmental biology · 2025Review
- PD-L1 knockout or ZG16 overexpression inhibits PDAC progression and modulates TAM polarization.Frontiers in immunology · 2025Article
- Endoplasmic Reticulum Stress in Cancer Progression: A Comprehensive Review of Its Role and Mechanisms.International journal of medical sciences · 2025Review
4 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 3 countries.
Funding
Abstract
In the tumor microenvironment, local immune dysregulation is driven in part by macrophages and dendritic cells that are polarized to a mixed proinflammatory/immune-suppressive phenotype. The unfolded protein response (UPR) is emerging as the possible origin of these events. Here we report that the inositol-requiring enzyme 1 (IRE1α) branch of the UPR is directly involved in the polarization of macrophages in vitro and in vivo, including the up-regulation of interleukin 6 (IL-6), IL-23, Arginase1, as well as surface expression of CD86 and programmed death ligand 1 (PD-L1). Macrophages in which the IRE1α/X-box binding protein 1 (Xbp1) axis is blocked pharmacologically or deleted genetically have significantly reduced polarization and CD86 and PD-L1 expression, which was induced independent of IFNγ signaling, suggesting a novel mechanism in PD-L1 regulation in macrophages. Mice with IRE1α- but not Xbp1-deficient macrophages showed greater survival than controls when implanted with B16.F10 melanoma cells. Remarkably, we found a significant association between the IRE1α gene signature and CD274 gene expression in tumor-infiltrating macrophages in humans. RNA sequencing (RNASeq) analysis showed that bone marrow-derived macrophages with IRE1α deletion lose the integrity of the gene connectivity characteristic of regulated IRE1α-dependent decay (RIDD) and the ability to activate CD274 gene expression. Thus, the IRE1α/Xbp1 axis drives the polarization of macrophages in the tumor microenvironment initiating a complex immune dysregulation leading to failure of local immune surveillance.
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Registered trials
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.