---
title: "Hypoxic Cancer Stem Cell–Immune Niches in the Tumor Microenvironment: Key Topics from a Missing Fu"
id: "frontiers-in-immunology-17-hypoxic-cancer-stem-cell-immune-niches-in-the-tumor-microenvironment-a"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-17-hypoxic-cancer-stem-cell-immune-niches-in-the-tumor-microenvironment-a"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1942424"
published_at: "2026-09-22T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Hypoxic Cancer Stem Cell–Immune Niches in the Tumor Microenvironment: Key Topics from a Missing Fu
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-17-hypoxic-cancer-stem-cell-immune-niches-in-the-tumor-microenvironment-a
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1942424)
- **Published At:** 2026-09-22T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The source record cites a systematic review titled "Hypoxic cancer stem cell–immune niches in the tumor microenvironment: a Systematic Review of mechanisms and therapeutic implications" published in Frontiers in Immunology, but the article text was not present in the provided source content. - The publicly visible metadata indicates the review addresses interactions among **hypoxic cancer stem cells**, the **tumor microenvironment**, and local **immune niches**, and it aims to synthesize mechanisms and therapeutic implications, per the title. - The retrieved page content contains only website navigation, journal sections, and links; no abstract, methods, results, conclusions, figures, or references from the systematic review were provided in the source body. - Because the article body and supporting details were not included in the source, specific mechanisms, data, study selection criteria, outcomes, and therapeutic recommendations are not available and therefore cannot be reported here. - Any discussion of likely subtopics (for example: hypoxia signaling, stem cell maintenance, immune evasion, niches composition, or therapeutic strategies) would be speculative beyond the title; the source did not supply those contents. - Users seeking the review's detailed findings, evidence synthesis, or clinical implications should consult the full article on the publisher site; the provided source did not include those sections. - This summary preserves the original intent and title of the work but explicitly notes that substantive content needed for a full clinical rewrite was not reported in the supplied source.
## Clinical Analysis & Structured Key Points
Frontiers | Hypoxic cancer stem cell–immune niches in the tumor microenvironment: a Systematic Review of mechanisms and therapeutic implications SYSTEMATIC REVIEW article Front. Immunol. , 22 September 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1942424 Published in Frontiers in Immunology Cancer Immunity and Immunotherapy 7 impact factor 11.3 citescore Part of a Research Topic Deciphering the Complex Interplay of Cancer Stem Cells and Immune Dynamics in the Tumor Microenvironment and Metastatic Niches Submission open 39k views 7 articles Editor & Reviewers Edited by C F Chuanwen Fan Reviewed by D S Dr. Sivapar V Mathan Y H Yixiang Hu Outline Figures and Tables Figure 1 View in article Figure 2 View in article Figure 3 View in article Table 1 Descriptive summary of component-specific methodological appraisal and principal limitations. View in article Table 2 Mechanistic and translational synthesis of hypoxia-driven CSC–immune interactions. View in article Table 3 Narrative comparison of support for hypoxia-driven CSC–immune reprogramming patterns. View in article SYSTEMATIC REVIEW article Front. Immunol. , 22 September 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1942424 Hypoxic cancer stem cell–immune niches in the tumor microenvironment: a Systematic Review of mechanisms and therapeutic implications P A Prasanna Appiya Premvignesh 1 A S Abubakker Siddiq Mohamed Hameed 2 I M Ibrahim Mustufa Topiwala 2 M N Mohammed Nayeem Shaji 2 L A Latifa Alsaad 3 * S M Safaa Mahmoud Mohamed Abdelkhalek 1,4 N R Nazeerullah Rahamathullah 1,5 * S C Salem Chouaib 5,6 1. Department of Biomedical Sciences, College of Medicine, Gulf Medical University, Ajman, United Arab Emirates 2. Faculty of Medicine, Medical University of Lublin, Lublin, Poland 3. Research and Graduate Studies, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates 4. Department of Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt 5. Thumbay Research Institute for Precision Medicine, Gulf Medical University, Ajman, United Arab Emirates 6. INSERM UMR 1186, Integrative Tumor Immunology and Cancer Immunotherapy, Gustave Roussy, University Paris-Saclay, Villejuif, France See more Article metrics View details Abstract 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. 1 Introduction Hypoxia is one of the defining characteristics of the tumor microenvironment (TME) in solid malignancies and develops when rapid tumor growth exceeds the capacity of the existing vasculature to supply adequate oxygen. Rather than functioning merely as a passive metabolic limitation, hypoxia initiates a broad range of adaptive transcriptional responses, primarily through activation of hypoxia-inducible factors (HIFs), particularly HIF-1α and HIF-2α ( 1 – 3 ). These transcriptional programs regulate numerous biological processes, including angiogenesis, metabolic reprogramming, epithelial-to-mesenchymal transition, invasion, immune evasion, and therapeutic resistance ( 2 , 4 ). Consequently, hypoxia has emerged as a central driver of tumor progression and adaptation within the hostile tumor microenvironment. Among the most important consequences of tumor hypoxia is the maintenance and expansion of cancer stem cells (CSCs). CSCs represent a specialized subpopulation of tumor cells characterized by enhanced self-renewal, tumor-initiating capacity, metastatic potential, and intrinsic resistance to conventional therapies ( 5 , 6 ). Hypoxic niches provide a favorable microenvironment for CSC maintenance by regulating stemness-associated transcription factors and signaling pathways, including NANOG, SOX2, OCT4, CD44, CD133, aldehyde dehydrogenase (ALDH) activity, Wnt/β-catenin signaling, and sphere-forming capacity ( 7 , 8 ). In addition to preserving pre-existing CSC populations, hypoxia may induce stem-like characteristics in differentiated tumor cells through cellular plasticity. These adaptive mechanisms contribute to tumor heterogeneity, therapeutic resistance, metastatic dissemination, and disease recurrence ( 9 , 10 ). Beyond promoting stemness, hypoxia profoundly influences the antitumor immune response. Hypoxia-associated signaling impairs immune surveillance through multiple mechanisms, including reduced natural killer (NK)-cell recognition, suppression of CD8 + cytotoxic T-cell function, altered immune-cell adhesion, and increased expression of immune checkpoint molecules ( 11 , 12 ). Simultaneously, hypoxia promotes the recruitment and functional polarization of immunosuppressive cell populations, including regulatory T cells (Tregs), tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and other suppressive myeloid compartments ( 13 , 14 ). Collectively, these alterations generate an immunosuppressive tumor microenvironment that favors tumor survival and disease progression. Importantly, accumulating evidence suggests that hypoxia-mediated regulation of CSCs and immune suppression are not independent phenomena but are closely interconnected. Hypoxic tumor regions may simultaneously promote CSC maintenance while suppressing antitumor immunity, thereby creating specialized microenvironmental niches that are stemness-permissive, immune-refractory, and highly resistant to therapy. Within these niches, CSCs may further reinforce immune evasion through immune checkpoint upregulation, cytokine-mediated immunosuppression, metabolic competition, and reciprocal interactions with macrophages and other myeloid cells ( 14 , 15 ). This reciprocal relationship suggests that hypoxia may function as a central coordinator linking CSC biology with immune escape mechanisms. The convergence of hypoxia, CSC plasticity, and immune suppression has particularly important implications for cancer immunotherapy. The efficacy of immune checkpoint inhibitors and other immunotherapeutic approaches depends on efficient antigen presentation, adequate immune-cell infiltration, sustained cytotoxic activity, and the absence of dominant immunosuppressive signals within the TME. However, hypoxic, CSC-enriched tumor regions frequently exhibit resistance to immune-mediated elimination because of impaired NK- and T-cell function, increased checkpoint expression, macrophage- and myeloid-mediated CSC support, cytokine-driven immunosuppression, and metabolic dysfunction ( 14 , 15 ). Understanding how hypoxia orchestrates CSC–immune interactions may therefore help explain why many tumors remain refractory to immunotherapy despite the presence of therapeutically targetable immune pathways. Although hypoxia, CSC biology, and immune evasion have each been extensively investigated, they have largely been reviewed as separate or only partially overlapping processes. This fragmented perspective limits our understanding of whether hypoxia-induced stemness and immune suppression represent parallel consequences of tumor stress or components of a coordinated adaptive program within the tumor microenvironment. Studies that simultaneously evaluate hypoxia-associated signaling, CSC phenotypes, and immune-related mechanisms within the same experimental system are particularly valuable because they provide direct evidence of mechanistic interactions rather than simple co-occurrence. Therefore, this systematic review synthesizes evidence from studies that concurrently investigated hypoxia or hypoxia-associated signaling, CSC or stemness phenotypes, and immune-related mechanisms within the same experimental framework. The review aims to identify recurrent molecular and cellular pathways linking hypoxia-associated CSC plasticity with immune modulation, critically evaluate the strength of evidence across heterogeneous experimental models, and assess the translational implications of these interactions for immune escape, immunotherapy resistance, and the development of tumor microenvironment-targeted therapeutic strategies. 2 Methods 2.1 Registration and reporting This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines ( 16 ) and prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD420261287704). The review was designed to synthesize mechanistic and translational evidence from studies that concurrently assessed hypoxia or hypoxia-associated signaling, CSC or stemness phenotypes, and immune-related mechanisms within the TME. 2.2 Review question and PICOS framework The review question was structured using an adapted PICOS framework suitable for mechanistic evidence synthesis. The population comprised experimental and translational cancer systems, including in vitro and ex vivo models, animal tumor models, human tumor tissue, serum extracellular vesicles, and public datasets supported by experimental validation. The exposure or intervention was hypoxia, hypoxia-associated signaling, or a clearly defined hypoxia-responsive system. Comparators included normoxic, untreated, genetic, pharmacologic, or other relevant controls where available; a single comparator was not mandatory because of the mechanistic scope of the review. Required outcomes included both CSC or stemness-related phenotypes and immune-related molecular, cellular, tissue-level, or functional outcomes. Eligible study designs included in vitro , ex vivo, animal, human tissue, dataset-supported, interventional, and mixed-design studies. 2.3 Search strategy A comprehensive systematic literature search was conducted in PubMed, Embase, Scopus, Web of Science, and Google Scholar to identify relevant studies published in English between 1 January 2010 and 31 January 2026. The search strategy combined three core concepts: (i) hypoxia or hypoxia-associated signaling, (ii) CSCs or stemness-related phenotypes, and (iii) immune modulation, immune suppression, or immune escape within the TME. For Google Scholar, the first 600 relevance-ranked records were recorded before duplicate removal and screened using the same two-team review process applied to the complete record set. Reference lists of relevant articles were also examined to identify potentially eligible reports, which were assessed against the same eligibility criteria. The complete database-specific search strategies, including search terms, Boolean operators, search dates, and applied limits, are provided in Supplementary Data Sheet 1 . 2.4 Eligibility criteria Studies were considered eligible if they concurrently evaluated all three predefined domains within the same study: (i) hypoxia or hypoxia-associated signaling, (ii) cancer stem cell (CSC) or stemness-related phenotypes, and (iii) immune-related molecular, cellular, tissue-level, or functional outcomes relevant to immune modulation. Eligible evidence of hypoxia included low-oxygen culture conditions, chemical stabilization of hypoxia-inducible signaling, activation of hypoxia-inducible factor (HIF)-1α or HIF-2α, hypoxia-associated gene expression, tumor hypoxia assessment, intermittent hypoxia, or other clearly defined hypoxia-responsive experimental systems. Eligible evidence of CSC or stemness phenotypes included the expression of CSC markers, stemness-associated transcription factors, sphere-forming ability, self-renewal capacity, tumor-initiating potential, lineage plasticity, metastatic CSC phenotypes, or the acquisition of stem-like characteristics. Eligible immune-related outcomes included immune-cell infiltration or function, immune-mediated cytotoxicity, cytokine signaling, macrophage polarization, myeloid-derived suppressor cell (MDSC)-mediated immunosuppression, Treg recruitment, immune checkpoint regulation, immune escape mechanisms, or suppression of innate and adaptive immune responses. Experimental in vitro , ex vivo, animal, translational human tissue, public dataset-supported, and mixed-design studies were eligible for inclusion. Interventional or therapeutic perturbation studies were included only if they directly evaluated all three predefined domains and provided mechanistic or translational evidence linking hypoxia-associated conditions with CSC or stemness phenotypes and immune-related outcomes. Studies were excluded if they were reviews, systematic reviews, meta-analyses, editorials, commentaries, study protocols, conference abstracts lacking sufficient primary data, non-cancer studies, case reports, or small case series. Studies that evaluated only one or two of the three required domains were also excluded. In addition, purely computational or dataset-only studies were excluded unless their findings were supported by experimental, animal, or human tissue validation. 2.5 Study selection and data extraction All retrieved records were imported into Zotero for reference management. Duplicate records were identified and manually verified before removal, after which the remaining records were exported to Rayyan for screening. Title and abstract screening was conducted through two parallel reviewer teams: Prasanna Appiya Premvignesh (PAP) and Mohammed Nayeem Shaji (MNS), and Abubakker Siddiq Mohamed Hameed (ASMH) and Ibrahim Mustufa Topiwala (IMT). Each team collectively assessed the complete set of 1,153 records, with the workload divided between its two members; consequently, every record received one assessment from each reviewer team. Team-level decisions were compared, and disagreements were resolved through discussion and consensus, with consultation of a senior author when required. The same two-team approach was used for full-text assessment of all 39 reports. Within each team, the reports were divided between the two reviewers, while both teams collectively covered the complete set; each report therefore received two separate eligibility assessments overall. Discrepant inclusion or exclusion decisions were discussed, and unresolved disagreements were referred to senior authors for adjudication. Eligibility at full text required concurrent evaluation of hypoxia or hypoxia-associated signaling, CSC or stemness phenotypes, and immune-related outcomes within the same experimental or translational study. Report-specific reasons for excluding the 25 full-text reports are provided in Supplementary Data Sheet 4 . Data extraction was independently performed by two reviewers (PAP and ASMH) for all 14 included studies using a standardized extraction framework. Extracted variables included study characteristics, country, cancer type, study model, hypoxia exposure or mechanism, CSC or stemness evidence, immune components or outcomes, proposed CSC–immune mechanisms, principal findings, and translational relevance. The independently completed extraction records were compared, and discrepancies were resolved through discussion and consensus; senior authors were consulted when clarification was required. 2.6 Methodological quality appraisal Given the methodological heterogeneity of the included studies, methodological appraisal was conducted separately for each applicable evidence component rather than by applying a single overall study-level score. Appraisal was independently performed by two reviewers (PAP and ASMH) for all included studies, their domain-level judgments were compared and reconciled through discussion, and the consolidated tables were reviewed by the senior authors for methodological and scientific consistency. Animal experimental components were appraised using domains informed by the Systematic Review Centre for Laboratory Animal Experimentation (SYRCLE) Risk of Bias Tool ( 17 ). Human tissue, serum extracellular vesicle, and public dataset-supported observational components were evaluated using Newcastle–Ottawa-style domains adapted to the available evidence ( 18 ). In vitro and ex vivo mechanistic components were assessed using predefined domains addressing clarity of hypoxia exposure or assessment, adequacy of CSC or stemness characterization, validity of immune-related assays, appropriateness of controls or comparators, and depth of mechanistic validation. No numerical scoring, cross-domain aggregation, or combined overall rating was performed. Detailed domain-level assessments are presented in Supplementary Tables S1 – S3 , and Table 1 provides a descriptive summary of the component-specific approaches and principal limitations. Table 1 Study Evidence components assessed Component-specific appraisal domains Principal component-specific considerations Wang et al. ( 20 ) In vitro TNBC models, human tissue, NK-cell assays, and xenograft models SYRCLE-informed animal domains; observational human-tissue domains; adapted mechanistic domains Animal randomization, allocation concealment, blinding, and sample-size justification were incompletely reported; human-tissue inference remained observational despite strong functional NK-cell assays. Geng et al. ( 21 ) In vitro colorectal CSC and NK-cell co-culture Adapted mechanistic domains Functional NK-cell assays were informative, but evidence relied mainly on one colorectal cancer cell-line model without animal or human-tumor validation. Dong et al. ( 24 ) Human glioma samples, public datasets, macrophage assays, and orthotopic xenograft SYRCLE-informed animal domains; observational human/dataset domains; adapted mechanistic domains Multimodal validation was extensive, but animal bias-reduction procedures were incompletely reported and macrophage modeling relied partly on U937-derived cells. Sami et al. ( 25 ) TNBC cell models, animal models, and human samples SYRCLE-informed animal domains; observational human-tissue domains; adapted mechanistic domains Multiple experimental platforms supported the mechanism, but randomization and blinding were incomplet
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