ArticleThe Journal of clinical investigation2023
Hemorrhage-activated NRF2 in tumor-associated macrophages drives cancer growth, invasion, and immunotherapy resistance.
Article in The Journal of clinical investigation, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 33 citations in OpenAlex.
- Rewiring redox defense: Nrf2-driven antioxidant signaling as a gateway to programmed cell death activation in colorectal cancer.Genes & diseases · 2027Review
- LAIR1 suppresses phagocytosis via SHP2/USP22-mediated MYH9 degradation in glioma-associated microglia/macrophages to drive immunosuppression.British journal of cancer · 2026Article
- Cantharidic acid causes mitochondrial dysfunction via the Nrf2/HO-1/GPX4 pathway to inhibit colorectal cancer progression.Histology and histopathology · 2026Article
- Multidrug resistance in cancer: current understandings and future perspective.Molecular biomedicine · 2026Review
- Sickle cell disease-associated pulmonary hypertension: an integrated framework linking pathologies, mechanisms, and clinical phenotypes.EBioMedicine · 2026Review
- Impact of heme on the therapeutic efficacy of anti-CD20 antibodies.The Journal of biological chemistry · 2026Article
- Tumor-derived DNA drives cancer-associated anemia by promoting reticulocyte clearance.Signal transduction and targeted therapy · 2026Article
- An ontogeny-cytokine code determines macrophage response polarity and tumor outcomes.Communications biology · 2026Article
- Establishment of a 3D Multicellular HCC Tumor Spheroid Model to Unravel Nrf2's Influence on the Tumor Immune Microenvironment.Bioengineering (Basel, Switzerland) · 2026Article
- IGSF9 promotes immunotherapy resistance in colon cancer by orchestrating an immunosuppressive tumor microenvironment and enables combinatorial targeting strategies.Biochemistry and biophysics reports · 2026Article
- Iron and metabolic rewiring in cancer.Oncogenesis · 2026Review
- Tumor-associated macrophages in cancer: from mechanisms to application.Molecular biomedicine · 2025Review
- HNRNPC reprograms cancer metabolism to drive acquired chemoresistance in colorectal cancer by repressing of Nrf2/SLC7A11-dependent ferroptosis.Cell communication and signaling : CCS · 2025Article
- Iron and the immune system.Nature reviews. Immunology · 2025Review
- Article
- Stress-NRF2 response axis polarizes tumor macrophages and undermines immunotherapy.Journal for immunotherapy of cancer · 2025Article
- Overlapping risk factors and pathogenic mechanisms in lung cancer and cardiovascular disease.Discover oncology · 2025Review
- Multiplexed Imaging Mass Cytometry Reveals Tumor-immune Microenvironment-dependent Hormone Receptor Expression in Adult-Type Ovarian Granulosa Cell Tumors.Cancer research communications · 2025Article
- Article
- NRF2 immunobiology in cancer: implications for immunotherapy and therapeutic targeting.Oncogene · 2025Review
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Microscopic hemorrhage is a common aspect of cancers, yet its potential role as an independent factor influencing both cancer progression and therapeutic response is largely ignored. Recognizing the essential function of macrophages in red blood cell disposal, we explored a pathway that connects intratumoral hemorrhage with the formation of cancer-promoting tumor-associated macrophages (TAMs). Using spatial transcriptomics, we found that NRF2-activated myeloid cells possessing characteristics of procancerous TAMs tend to cluster in perinecrotic hemorrhagic tumor regions. These cells resembled antiinflammatory erythrophagocytic macrophages. We identified heme, a red blood cell metabolite, as a pivotal microenvironmental factor steering macrophages toward protumorigenic activities. Single-cell RNA-Seq and functional assays of TAMs in 3D cell culture spheroids revealed how elevated intracellular heme signals via the transcription factor NRF2 to induce cancer-promoting TAMs. These TAMs stabilized epithelial-mesenchymal transition, enhancing cancer invasiveness and metastatic potential. Additionally, NRF2-activated macrophages exhibited resistance to reprogramming by IFN-γ and anti-CD40 antibodies, reducing their tumoricidal capacity. Furthermore, MC38 colon adenocarcinoma-bearing mice with NRF2 constitutively activated in leukocytes were resistant to anti-CD40 immunotherapy. Overall, our findings emphasize hemorrhage-activated NRF2 in TAMs as a driver of cancer progression, suggesting that targeting this pathway could offer new strategies to enhance cancer immunity and overcome therapy resistance.
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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.