Evidence map›Paper›PMID 34559989›Full record

ArticleCell metabolism2021

Tumor-derived exosomes drive immunosuppressive macrophages in a pre-metastatic niche through glycolytic dominant metabolic reprogramming.

Samantha M Morrissey, Fan Zhang, Chuanlin Ding, Diego Elias Montoya-Durango, Xiaoling Hu, Chenghui Yang, Zhen Wang, Fang Yuan, Matthew Fox, Huang-Ge Zhang and 9 more

Open access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell metabolism, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 397 papers, 3 of them syntheses that pooled it.

0numbers the graph read from it
0cells of the map it votes in
397citing papers in PubMed, 3 pooled it
32.2field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

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.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

397 citing papers in PubMed, 3 syntheses or guidelines pooled it, 560 citations in OpenAlex.

  1. Pooled it
  2. Correlation between exosomal PD-L1 and prognosis in patients with cancer: a systematic review and meta-analysis.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2025
    Pooled it
  3. Pooled it
  4. Review
  5. Niches in cancer: from primary tumors to metastatic disease.Journal of hematology & oncology · 2026
    Review
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  11. Article
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  15. Exosome-mediated siRNA delivery in cancer: Loading strategies, targeting approaches, and therapeutic outcomes.Daru : journal of Faculty of Pharmacy, Tehran University of Medical Sciences · 2026
    Review
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337 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

19 authors at 2 institutions in 2 countries.

Samantha M MorrisseyDepartment of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY, USA; Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.
Fan ZhangDivision of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA; Jiangxi Provincial Children's Hospital, Jiangxi, Nanchang, China.
Chuanlin DingDivision of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.
Diego Elias Montoya-DurangoDivision of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.
Xiaoling HuDivision of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.
Chenghui YangDepartment of Breast Surgery, Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Cancer Research Institute of Zhejiang University, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, China; Department of Breast Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China.
Zhen WangDepartment of Breast Surgery, Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Cancer Research Institute of Zhejiang University, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, China.
Fang YuanDepartment of Chemistry, University of Louisville, Louisville, KY, USA.
Matthew FoxDepartment of Cardiovascular and Thoracic Surgery, University of Louisville School of Medicine, Louisville, KY, USA.
Huang-Ge ZhangDepartment of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY, USA.
Haixun GuoDepartment of Radiology, University of Louisville School of Medicine, Louisville, KY, USA.
David TieriDepartment of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, USA.
Maiying KongDepartment of Bioinformatics and Biostatistics, University of Louisville, School of Medicine, Louisville, KY, USA.
Corey T WatsonDepartment of Biochemistry and Molecular Genetics, University of Louisville School of Medicine, Louisville, KY, USA.
Robert A MitchellDivision of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.
Xiang ZhangDepartment of Chemistry, University of Louisville, Louisville, KY, USA.
Kelly M McMastersDivision of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA.
Jian HuangDepartment of Breast Surgery, Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Cancer Research Institute of Zhejiang University, The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang, China.
Jun YanDepartment of Microbiology and Immunology, University of Louisville School of Medicine, Louisville, KY, USA; Division of Immunotherapy, The Hiram C. Polk, Jr., MD Department of Surgery, Immuno-Oncology Program, Brown Cancer Center, University of Louisville School of Medicine, Louisville, KY, USA. Electronic address: jun.yan@louisville.edu.
University of Louisville · USZhejiang University · CN

Funding

The role of ECM-mediated mechanosignaling on regional immunosuppression in GBMP20GM135004 · NIGMS · UNIVERSITY OF LOUISVILLE · PI JUN YAN · 2020 to 2026
$21.1M
Systems Biochemistry in Lung Cancer: Toward a Mechanistic Understanding of NSCLCP01CA163223 · NCI · UNIVERSITY OF LOUISVILLE · PI FAN, TERESA WHEI-MEI, HIGASHI, RICHARD M · 2013 to 2017
$6.5M
Transcriptional Regulation of Immunosuppressive Macrophages by c-Maf in CancerR01CA213990 · NCI · UNIVERSITY OF LOUISVILLE · PI YAN, JUN · 2017 to 2021
$1.8M
Regulation of dermal gammadelta T cells by microbial pathogens/commensals in health and psoriasisR01AI128818 · NIAID · UNIVERSITY OF LOUISVILLE · PI YAN, JUN · 2017 to 2021
$974k
NCI NIH HHS P01 CA163223NCI NIH HHS R01 CA213990NIAID NIH HHS R01 AI128818NIGMS NIH HHS P20 GM135004
6 · The paper itself

Abstract

One of the defining characteristics of a pre-metastatic niche, a fundamental requirement for primary tumor metastasis, is infiltration of immunosuppressive macrophages. How these macrophages acquire their phenotype remains largely unexplored. Here, we demonstrate that tumor-derived exosomes (TDEs) polarize macrophages toward an immunosuppressive phenotype characterized by increased PD-L1 expression through NF-kB-dependent, glycolytic-dominant metabolic reprogramming. TDE signaling through TLR2 and NF-κB leads to increased glucose uptake. TDEs also stimulate elevated NOS2, which inhibits mitochondrial oxidative phosphorylation resulting in increased conversion of pyruvate to lactate. Lactate feeds back on NF-κB, further increasing PD-L1. Analysis of metastasis-negative lymph nodes of non-small-cell lung cancer patients revealed that macrophage PD-L1 positively correlates with levels of GLUT-1 and vesicle release gene YKT6 from primary tumors. Collectively, our study provides a novel mechanism by which macrophages within a pre-metastatic niche acquire their immunosuppressive phenotype and identifies an important link among exosomes, metabolism, and metastasis.

Indexed as

Carcinoma, Non-Small-Cell LungExosomesLung NeoplasmsCell Line, TumorGlycolysisHumansMacrophagesR-SNARE ProteinsTumor MicroenvironmentR-SNARE ProteinsYKT6 protein, humanexosomesglycolysisimmunosuppressionlactatemetastasisNF-kBPD-L1

Identifiers

PMID34559989
PMCPMC8506837
OpenAlexW3201325011

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

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.