Immune cell-derived exosomes in the tumor microenvironment: mechanisms of immune evasion and emerging therapeutic strategies in cancer immunotherapy
4 affiliations
- 1Prince Fahad Bin Sultan Chair for Biomedical Research, University of Tabuk
- 2Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, University of Tabuk
- 3Department of Surgical Oncology, Faculty of Medicine, University of Tabuk
- 4Department of Biology, Faculty of Science, University of Tabuk
Abstract
Tumor-released exosomes have emerged from the shadows of “cellular dust” to be recognized as pivotal mediators of intercellular communication within the tumor microenvironment (TME). These nano-sized vesicles (30–150 nm) carry a complex cargo of proteins, lipids, and nucleic acids that profoundly reshape anti-tumor immunity. This review comprehensively examines the dualistic nature of immune cell-derived exosomes in cancer progression, with particular focus on exosomes originating from B lymphoma cells, T lymphocytes, natural killer (NK) cells, and myeloid-derived suppressor cell lineages including tumor-associated macrophages (TAMs), mast cells, and neutrophils. We delineate the mechanistic pathways through which these exosomes disrupt the cancer immunity cycle suppressing CD8+ T cell activation via PD-L1/PD-1 engagement, inducing lymphocyte apoptosis through FasL and TRAIL, promoting regulatory T cell expansion, polarizing macrophages toward the M2 immunosuppressive phenotype, and establishing pre-metastatic niches through MMP-mediated extracellular matrix remodeling. The molecular machinery governing exosome biogenesis including ESCRT-dependent and ceramide-mediated pathways is critically reviewed, alongside the selective packaging mechanisms that concentrate immunosuppressive miRNAs (miR-155, miR-21, miR-23a, miR-223) into exosomal compartments. Importantly, we highlight the emerging therapeutic premises targeting these vesicles: pharmacological inhibition of exosome secretion (GW4869, Rab27a knockdown), checkpoint blockade reversing exosomal PD-L1-mediated T cell exhaustion, and the engineering of immunostimulatory exosomes as cell-free cancer vaccines establishing exosomes not merely as biomarkers of disease progression but as actionable therapeutic targets. The clinical translation of exosome-based diagnostics including liquid biopsy platforms detecting circulating tumor-derived exosomes and therapeutics that include engineered exosomes delivering immunomodulatory cargo represents a frontier in precision cancer immunotherapy.
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BibTeX
@article{mir2026immune,
title = {{Immune cell-derived exosomes in the tumor microenvironment: mechanisms of immune evasion and emerging therapeutic strategies in cancer immunotherapy}},
author = {Rashid Mir and Mohammad Fahad Ullah and Mamdoh S. Moawadh and Faisal H. Altemani and Jameel Barnawi and Naseh A. Algehainy and Mohammed M. Jalal and Malik A. Altayar and Reema M. Almotairi and Faris J. Tayeb and Ruqaiah I. Bedaiwi and Kholoud S. Almasoudi and Ibrahim Altedlawi Albalawi and Aeshah A. Awaji},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1902856},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1902856/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Immune cell-derived exosomes in the tumor microenvironment: mechanisms of immune evasion and emerging therapeutic strategies in cancer immunotherapy
AU - Rashid Mir
AU - Mohammad Fahad Ullah
AU - Mamdoh S. Moawadh
AU - Faisal H. Altemani
AU - Jameel Barnawi
AU - Naseh A. Algehainy
AU - Mohammed M. Jalal
AU - Malik A. Altayar
AU - Reema M. Almotairi
AU - Faris J. Tayeb
AU - Ruqaiah I. Bedaiwi
AU - Kholoud S. Almasoudi
AU - Ibrahim Altedlawi Albalawi
AU - Aeshah A. Awaji
PY - 2026
DA - 2026/10/14
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1902856
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1902856/full
AB - Tumor-released exosomes have emerged from the shadows of “cellular dust” to be recognized as pivotal mediators of intercellular communication within the tumor microenvironment (TME). These nano-sized vesicles (30–150 nm) carry a complex cargo of proteins, lipids, and nucleic acids that profoundly reshape anti-tumor immunity. This review comprehensively examines the dualistic nature of immune cell-derived exosomes in cancer progression, with particular focus on exosomes originating from B lymphoma cells, T lymphocytes, natural killer (NK) cells, and myeloid-derived suppressor cell lineages including tumor-associated macrophages (TAMs), mast cells, and neutrophils. We delineate the mechanistic pathways through which these exosomes disrupt the cancer immunity cycle suppressing CD8+ T cell activation via PD-L1/PD-1 engagement, inducing lymphocyte apoptosis through FasL and TRAIL, promoting regulatory T cell expansion, polarizing macrophages toward the M2 immunosuppressive phenotype, and establishing pre-metastatic niches through MMP-mediated extracellular matrix remodeling. The molecular machinery governing exosome biogenesis including ESCRT-dependent and ceramide-mediated pathways is critically reviewed, alongside the selective packaging mechanisms that concentrate immunosuppressive miRNAs (miR-155, miR-21, miR-23a, miR-223) into exosomal compartments. Importantly, we highlight the emerging therapeutic premises targeting these vesicles: pharmacological inhibition of exosome secretion (GW4869, Rab27a knockdown), checkpoint blockade reversing exosomal PD-L1-mediated T cell exhaustion, and the engineering of immunostimulatory exosomes as cell-free cancer vaccines establishing exosomes not merely as biomarkers of disease progression but as actionable therapeutic targets. The clinical translation of exosome-based diagnostics including liquid biopsy platforms detecting circulating tumor-derived exosomes and therapeutics that include engineered exosomes delivering immunomodulatory cargo represents a frontier in precision cancer immunotherapy.
SN - 1664-3224
ER -