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Review | Open Access

Cancer Drug Resistance

Cheng et al. Cancer Drug Resist. 2025;8:46 DOI:10.20517/cdr.2025.132

Targeting the hypoxia signaling pathway with
nanomedicine to reverse immunotherapy resistance

Xiaoliang Cheng 1,2,3,# , Peixing Wang , Hongqiang Lyu , Yonghyun Lee , Juyoung Yoon , Haiyan Dong 1
3,6
4,#
2,6
5
Keywords:
Immunotherapy resistance,
HIF-1a, tumor-associated
macrophages, T cell
exhaustion, immune
evasion, vascular
normalization,
nanomedicine

Citation: Cheng X, Wang P,
Lyu H, Lee Y, Yoon J, Dong H.
Targeting the hypoxia
signaling pathway with
nanomedicine to reverse
immunotherapy resistance.
Cancer Drug Resist.
2025;8:46.
https://dx.doi.org/10.20517
/cdr.2025.132
Abstract
Received: 3 Jul 2025 Immunotherapy has emerged as a major therapeutic strategy for cancer; however,
First Decision: 29 Jul immunotherapy resistance remains a significant challenge. Hypoxia, a key hallmark of the
2025 tumor microenvironment resulting from the imbalance between the high oxygen demand of
Revised: 12 Aug 2025
Accepted: 21 Aug 2025 rapidly proliferating cancer cells and the limited supply from abnormal blood vessels, plays
Published: 2 Sep 2025 a central role in driving immunotherapy resistance. Hypoxia-inducible factor-1α (HIF-1α)
and its downstream signaling pathways contribute to this resistance by promoting
Academic Editor: macrophage polarization toward the protumorigenic M2 phenotype, inducing T cell
Chiara Riganti exhaustion, facilitating immune evasion, enhancing angiogenesis, and activating other
Copy Editor:
Pei-Yun Wang resistance mechanisms. The review highlights the mechanisms by which hypoxia regulates
Production Editor: resistance to immunotherapy and provides a comprehensive overview of
Pei-Yun Wang
nanotechnology-based strategies designed to counteract hypoxia-induced resistance.

1 Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi, China.
2 College of Pharmacy, Ewha Womans University, Seoul 03760, South Korea.
3 Department of Chemistry and Nanoscience, Ewha Womans University, Seoul 03760, South Korea.
4 Department of Materials Science and Engineering, Yonsei University, Seoul 03722, South Korea.
5 School of Automation Science and Engineering, Faculty of Electronic and Information Engineering, Xi’an Jiaotong University, Xi’an 710049,
Shaanxi, China.
6 Graduate Program in Innovative Biomaterials Convergence, Ewha Womans University, Seoul 03760, South Korea.
# Authors contributed equally.

Correspondence to: Dr. Haiyan Dong, Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061,
Shaanxi, China. E-mail: donghy@mail.xjtu.edu.cn; Prof. Juyoung Yoon, Department of Chemistry and Nanoscience, Ewha Womans
University, Seoul 03760, South Korea. E-mail: jyoon@ewha.ac.kr; Prof. Yonghyun Lee, College of Pharmacy, Ewha Womans University,
Seoul 03760, South Korea. E-mail: y.lee@ewha.ac.kr

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