Impact of chemotherapeutic agents on liver microenvironment: oxaliplatin create a pro-metastatic landscape
Open accessAbstract
Background: Chemotherapeutic agents are used to control tumor proliferation. However, their influence in the pre-metastatic niche of target organs has not been well studied. Oxaliplatin (OXA) is a drug applied in standard treatments of colorectal cancer (CRC), while the direct effect of which on the pre-metastatic microenvironment of the liver remains unclear. Methods: Models of liver metastases were established with luciferase expressing CT26 cells in BALB/c and BALB/c-nude mice. Single-cell RNA Sequencing was performed to examine the immune microenvironment in the liver elicited by OXA. Immunofluorescence and flowcytometry were utilized to confirm the changes in the number of immune cells. LDH, CellTrace CFSE Cell Proliferation and apoptosis assays were conducted to explore the impact of OXA on T cells ex vivo. The correlation between chemotherapy-related lymphopenia and metastases was assessed by meta-analysis. Results: Herein we discovered that administration of OXA prior to the occurrence of liver metastasis actually accelerated tumor development and colonization in the liver. Single-cell RNA sequencing revealed that the landscape of the liver immune microenvironment had been changed to immunosuppressive phenotype. Macrophages after the treatment of OXA exhibited a high ability to inhibit the activation of T cells. Further investigation revealed a significant decrease in the number of T cells in the liver, particularly CD8 + T cells with reduced capacity of proliferation, activation, and killing. When mice were treated with T cell supplementation, the OXA-induced metastasis was notably abolished, indicating that the OXA-primed liver microenvironment could be reversed by the infusion of T cells. Consistent with our findings in mice, a meta-analysis was performed to verify that chemotherapy-related lymphopenia was associated with an inferior prognosis related with high incidence of metastasis, suggesting the pivotal role of chemotherapy in pre-metastatic niche formation. Furthermore, a notable reduction in the count of both macrophages and T cells was observed in the liver of colorectal cancer (CRC) patient undergoing OXA-based chemotherapy. Conclusions: Our findings proposed that immunosuppressive microenvironment in liver induced by OXA enhanced liver metastasis of colorectal cancer, which highlighted a new consideration to balance the pro metastases and anti-cancer possibility of OXA treatment.
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Senescence is a possible cause of decreased liver function in the sinusoidal area.
“These findings align with the known liver injury and sinusoidal obstruction caused by oxaliplatin,85,86,87 suggesting senescence as a possible cause of decreased liver function in the sinusoidal area.”
From Cellular senescence in human liver under normal aging and cancer (2026) · cites this paper as [86]
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- Authors
- Ma, Y., Guo, C., Wang, X., Wei, X., & Ma, J.
- Affiliations
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Corresponding author
- Wei, Xundong
- Ma, Jie
- Venue
- Journal of Experimental & Clinical Cancer Research
- Published
- 2023-09-11
- Volume
- 42
- Issue
- 1
- Pages
- 237-237
- ISSN
- 0392-9078 (ISSN-L)
- 1756-9966
- PMC
- PMC10494354
- OpenAlex
- W4386605047
- Cited by
- 29
- References
- 50
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 8
- FWCI
- 0.94
- Type
- journal article
- Language
- en
- Update notices
- correction (2025-12-27)
- Open access
- gold
- doi.org
- Locations
- Journal of Experimental & Clinical Cancer Research (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National High Level Hospital Clinical Research Funding (BJ-2022-118)
- CAMS Innovation Fund for Medical Sciences (2021-I2M-1-050)
- National Natural Science Foundation of China (82173109)
- Guangxi science and technology base and talent Special projects (AD21220001, AD22035054)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Keywords
- oxaliplatin, colorectal cancer, liver metastasis, pre-metastatic niche, tumor microenvironment, immunosuppression, CD8+ T cells, tumor-associated macrophages, T cell suppression, adoptive T cell therapy, anticancer agents
- MeSH terms
- Oxaliplatin, Animals, Immunosuppressive Agents, Liver Neoplasms, Mice, Nude, Colorectal Neoplasms, CD8-Positive T-Lymphocytes, Mice, 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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