Frontiers in immunology · 2026
Hypoxic cancer stem cell-immune niches in the tumor microenvironment: a Systematic Review of mechanisms and therapeutic implications.
СтатьяСистематический обзорНазвание и аннотация: Перевод пока не подготовлен
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Appiya Premvignesh Prasanna, Mohamed Hameed Abubakker Siddiq, Mustufa Topiwala Ibrahim, Shaji Mohammed Nayeem, Alsaad Latifa, Mohamed Abdelkhalek Safaa Mahmoud, Rahamathullah Nazeerullah, Chouaib Salem
Аннотация
BACKGROUND: Hypoxia, cancer stem cell (CSC) plasticity, and immune suppression are established features of the tumor microenvironment, but their integration within the same biological systems has not been comprehensively synthesized. This systematic review evaluated whether hypoxia or hypoxia-associated signaling coordinates CSC or stemness phenotypes with immune-related mechanisms.
METHODS: PubMed, Embase, Scopus, Web of Science, and Google Scholar were searched for English-language studies published from 1 January 2010 to 31 January 2026. Eligible studies were required to evaluate hypoxia or hypoxia-associated signaling, CSC or stemness phenotypes, and immune-related outcomes within the same experimental or translational study. Of 1,569 records identified, 39 reports underwent full-text assessment and 14 studies were included.
RESULTS: Hypoxia-associated conditions were recurrently linked to CSC enrichment, self-renewal, epithelial-to-mesenchymal transition, tumorigenicity, metastatic potential, immune suppression, and therapeutic resistance. Four context-dependent patterns emerged: impaired natural killer, cytokine-induced killer, and CD8-positive T-cell function; myeloid- and macrophage-mediated reinforcement of CSC states through polarization, cytokine signaling, extracellular vesicles, cellular transfer, and stromal or vascular remodeling; checkpoint-associated and adaptive immune suppression involving PD-L1, CD47, regulatory T cells, and myeloid-derived suppressor cells; and an integrated hypoxic CSC-immune niche phenotype. Preclinical intervention studies indicated that selected pathways may be therapeutically modifiable, although the evidence remained predominantly experimental.
CONCLUSIONS: Hypoxia appears to act as a coordinating microenvironmental pressure linking CSC plasticity with immune dysfunction in selected tumor contexts. The proposed hypoxic CSC-immune niche is a mechanistic framework rather than evidence of a universal pathway and requires validation using spatially resolved human tumors, patient-derived immune models, and treatment-response-linked cohorts.
SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/view/CRD420261287704, identifier CRD420261287704.
METHODS: PubMed, Embase, Scopus, Web of Science, and Google Scholar were searched for English-language studies published from 1 January 2010 to 31 January 2026. Eligible studies were required to evaluate hypoxia or hypoxia-associated signaling, CSC or stemness phenotypes, and immune-related outcomes within the same experimental or translational study. Of 1,569 records identified, 39 reports underwent full-text assessment and 14 studies were included.
RESULTS: Hypoxia-associated conditions were recurrently linked to CSC enrichment, self-renewal, epithelial-to-mesenchymal transition, tumorigenicity, metastatic potential, immune suppression, and therapeutic resistance. Four context-dependent patterns emerged: impaired natural killer, cytokine-induced killer, and CD8-positive T-cell function; myeloid- and macrophage-mediated reinforcement of CSC states through polarization, cytokine signaling, extracellular vesicles, cellular transfer, and stromal or vascular remodeling; checkpoint-associated and adaptive immune suppression involving PD-L1, CD47, regulatory T cells, and myeloid-derived suppressor cells; and an integrated hypoxic CSC-immune niche phenotype. Preclinical intervention studies indicated that selected pathways may be therapeutically modifiable, although the evidence remained predominantly experimental.
CONCLUSIONS: Hypoxia appears to act as a coordinating microenvironmental pressure linking CSC plasticity with immune dysfunction in selected tumor contexts. The proposed hypoxic CSC-immune niche is a mechanistic framework rather than evidence of a universal pathway and requires validation using spatially resolved human tumors, patient-derived immune models, and treatment-response-linked cohorts.
SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/PROSPERO/view/CRD420261287704, identifier CRD420261287704.