Cancer Research and Treatment

Review Article

Understanding Immune Cell Adaptation to Tumor Hypoxia for Maximized Therapeutic Efficacy of Immunotherapy: Biology and Non-invasive Imaging Application: Taerim Oh, Minwoo Kim, Gi-Sue Kang, Sung-Joon Ye, Changhoon Choi, Won Park, Michael Hay, Hiroshi Hirata, G-One Ahn; Cancer Res Treat. 2026;58(1):26-47. Published online April 29, 2025; DOI: https://doi.org/10.4143/crt.2025.200

It is extensively documented that tumor hypoxia contributes to the failure of chemotherapy and radiotherapy. Recent evidence suggests that hypoxia is also closely involved in the resistance to immunotherapy. In this review, we highlight how immune cells that are essential for the maximized immunotherapy efficacy, including cytotoxic T cells, dendritic cells, and natural killer cells, can adapt to tumor hypoxia. We then outline previous attempts targeting tumor hypoxia (for example, modulators of tumor cell oxygen consumption, perfusion modulators, hypoxia-activated prodrugs, hypoxia-inducible factor inhibitors, and hypoxia-responsive chimeric antigen receptor T cells) discussing how these approaches have resulted in an improvement of the antitumor response to immunotherapy in preclinical or clinical settings. Lastly, we review various non-invasive techniques to detect the tumor hypoxia and immune responses. We believe that an integration of the biological knowledge of immune cell adaptation to tumor hypoxia with the cutting edge non-invasive imaging technologies may ultimately allow us not only to select for patients who would benefit the most from the immunotherapy but also to monitor their responses in a real-time manner so that we can offer them an optimal personalized medicine in the clinic.

Citations

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Fucoidans as multifunctional marine polysaccharide platforms: From nutritional supplements to advanced drug delivery for cancer therapy
Yuning Liu, Lin Long, Jianhua Zang, Chuanlong Guo, Jun Xiao, Gaoyang Lin
International Journal of Pharmaceutics: X.2026; 11: 100546. CrossRef
Heterogeneity, Measurement, and Clinical Implications of Oxygenation, Cell Signaling, and Redox Biology in Glioblastoma and Adult Diffuse Gliomas, with Context from Other Brain Tumors
Arabinda Das, Julian E. Bailes, Ann Barlow, Daniil P. Aksenov
Antioxidants.2026; 15(4): 505. CrossRef

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Original Article

General

Targeted Liquid Biopsy Using Irradiation to Facilitate the Release of Cell-Free DNA from a Spatially Aimed Tumor Tissue: Jae Myoung Noh, Yeon Jeong Kim, Ho Yun Lee, Changhoon Choi, Won-Gyun Ahn, Taeseob Lee, Hongryull Pyo, Jee Hyun Park, Donghyun Park, Woong-Yang Park; Cancer Res Treat. 2022;54(1):40-53. Published online May 25, 2021; DOI: https://doi.org/10.4143/crt.2021.151

Abstract PDF Supplementary Material PubReader ePub

Purpose
We investigated the feasibility of using an anatomically localized, target-enriched liquid biopsy (TLB) in mouse models of lung cancer.
Materials and Methods
After irradiating xenograft mouse with human lung cancer cell lines, H1299 (NRAS proto-oncogene, GTPase [NRAS] Q61K) and HCC827 (epidermal growth factor receptor [EGFR] E746-750del), circulating (cell-free) tumor DNA (ctDNA) levels were monitored with quantitative polymerase chain reaction on human long interspersed nuclear element-1 and cell line-specific mutations. We checked dose-dependency at 6, 12, or 18 Gy to each tumor-bearing mouse leg using 6-MV photon beams. We also analyzed ctDNA of lung cancer patients by LiquidSCAN, a targeted deep sequencing to validated the clinical performances of TLB method.
Results
Irradiation could enhance the detection sensitivity of NRAS Q61K in the plasma sample of H1299-xenograft mouse to 4.5- fold. While cell-free DNA (cfDNA) level was not changed at 6 Gy, ctDNA level was increased upon irradiation. Using double-xenograft mouse with H1299 and HCC827, ctDNA polymerase chain reaction analysis with local irradiation in each region could specify mutation type matched to transplanted cell types, proposing an anatomically localized, TLB. Furthermore, when we performed targeted deep sequencing of cfDNA to monitor ctDNA level in 11 patients with lung cancer who underwent radiotherapy, the average ctDNA level was increased within a week after the start of radiotherapy.
Conclusion
TLB using irradiation could temporarily amplify ctDNA release in xenograft mouse and lung cancer patients, which enables us to develop theragnostic method for cancer patients with accurate ctDNA detection.

Citations

Citations to this article as recorded by

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Basic Science with Preclinical Models to Investigate and Develop Liquid Biopsy: What Are the Available Data and Is It a Fruitful Approach?
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