A clinically acceptable strategy for sensitizing anti-PD-1 treatment by hypoxia relief
Abstract
The hypoxic tumor microenvironment (TME) hinders the effectiveness of immunotherapy. Alleviating tumor hypoxia to improve the efficacy of immune checkpoint inhibitors (ICIs) represented by programmed cell death protein 1 (PD-1) antibody has become a meaningful strategy. In this study, we adopted three methods to alleviate hypoxia, including direct oxygen delivery using two different carriers and an indirect way involving HIF-1α inhibition. Both in vivo and in vitro experiments showed that liposomes modified with perfluorocarbon or hemoglobin (PFC@lipo or Hb@lipo) were able to efficiently load and release oxygen, relieving tumor hypoxia. However, the gas release behavior of PFC@lipo was uncontrollable, which might induce acute hyperoxia side effects during intravenous injection and reduce its biosafety. In contrast, whether administered locally or systemically, Hb@lipo revealed high animal tolerance, and was much safer than commercial HIF-1α inhibitor (PX-478), displaying prospects as a promising oxygen carrier for clinical practice. Pharmacodynamic experiments suggested that Hb@lipo helped PD-1 antibody break the therapeutic bottleneck and significantly inhibited the progression of 4 T1 breast cancer. But in CT26 colon cancer, the combination therapy failed to suppress tumor growth. After in-depth analysis and comparison, we found that the ratio of M1/M2 tumor associated macrophages (TAMs) between these two tumor models were dramatically different. And the lower M1/M2 ratio in CT26 tumors limited the anti-tumor effect of combination therapy. In this study, three methods for alleviating tumor hypoxia were compared from the perspectives of biosafety, efficacy and clinical applicability. Among them, Hb@lipo stood out, and its combined use with PD-1 antibody exhibit a distinct synergistic suppression effect on tumors with more M1 macrophages presented in the microenvironment. Our work provided a good reference for improving the efficacy of PD-1 antibody by alleviating tumor hypoxia.
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Alleviating the hypoxic TME may be an effective strategy to improve tumor immunotherapy represented by PD-1 blockade.
“The above findings suggest that alleviating the hypoxic TME may be an effective strategy to improve tumor immunotherapy represented by PD‐1 blockade (Figure 7). 421”
From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [421]
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- Authors
- Jiang, M., Qin, B., Luo, L., Li, X., Shi, Y., Zhang, J., Luo, Z., Zhu, C., Guan, G., Du, Y., & You, J.
- Affiliations
- Zhejiang University (CN)
- Corresponding author
- You, Jian
- Venue
- Journal of Controlled Release
- Publisher
- Elsevier BV
- Published
- 2021-07
- Volume
- 335
- Pages
- 408-419
- ISSN
- 0168-3659 (ISSN-L)
- OpenAlex
- W3170224693
- Cited by
- 30
- References
- 62
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 5 · 2023: 5 · 2022: 11 · 2021: 2
- FWCI
- 2.11
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Journal of Controlled Release (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Physical Sciences › Engineering › Biomedical Engineering › Nanoplatforms for cancer theranostics
- Keywords
- tumor hypoxia, tumor microenvironment, anti-PD-1, immune checkpoint inhibitors, oxygen carriers, liposomes, perfluorocarbons, hemoglobin, HIF-1α inhibition, tumor-associated macrophages, M1/M2 macrophage ratio, breast cancer, colon cancer, combination immunotherapy
- MeSH terms
- Tumor Hypoxia, Animals, Hypoxia, Breast Neoplasms, Female, Humans, Immunotherapy, Cell Line, Tumor, Tumor Microenvironment
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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