AccScience Publishing / HM / Online First / DOI: 10.36922/HM025500003
REVIEW ARTICLE

Challenges and beyond: Targeting hypoxia-inducible factors for anti-tumor immunity restoration

Samantha H. Y. Leung1† Di Wang1† Qianya Wan1* Ming-Liang He1*
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1 Department of Biomedical Sciences, College of Biomedicine, City University of Hong Kong, Hong Kong SAR, China
†These authors contributed equally to this work.
Received: 11 December 2025 | Revised: 22 January 2026 | Accepted: 13 February 2026 | Published online: 17 April 2026
© 2026 by the Author(s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution -Noncommercial 4.0 International License (CC-by the license) ( https://creativecommons.org/licenses/by-nc/4.0/ )
Abstract

Hypoxia-inducible factors (HIFs) are key regulators linked to hypoxia, metabolism, and tumor immunity. Current studies on HIF-targeted cancer immunotherapy primarily focus on single cell types or pathways and often lack subunit selectivity, making therapeutic outcomes difficult to predict. In this article, we review how HIF-1α and HIF-2α shape the immunosuppressive tumor microenvironment across metabolism, vasculature, and immune cell programs. We explore the advantages and challenges of current strategies, including HIF inhibition combined with immune checkpoint blockade, adoptive cell therapy, regulatory T cell or myeloid modulation, and vascular normalization, noting that existing evidence remains limited and fragmented. We propose that rational HIF targeting may support tumor immunity through a coordinated modulation of multiple axes rather than targeting individual pathways in isolation. Finally, we introduce two forward-looking directions: an organoid-based microfluidic tumor-on-a-chip model as a platform to systematically evaluate HIF-targeted interventions, and rhythm-aligned, intermittent HIF modulation as a potential strategy to reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy efficacy.

Keywords
Hypoxia-inducible factors
Tumor hypoxia
Immune microenvironment
Cancer immunotherapy
Funding
This study was partially supported by ConRes-RO (9231572) of City University of Hong Kong, and RGC Collaborative Research Fund (C1018-23G) of the Hong Kong Special Administrative Region.
Conflict of interest
Ming-Liang He is an Associate Editor of this journal, but was not in any way involved in the editorial and peer-review process conducted for this paper, directly or indirectly. Separately, other authors declared that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.
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