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Published on: November 26, 2010
HIF-1α Mediates Immunosuppression and Chemoresistance in Colorectal Cancer by Inhibiting CXCL9, -10 and -11
Yixi Su1, Jiaqi Liu2, Yu Tian2
1Department of Clinical Laboratory, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Department of General Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Guangdong Institute of Gastroenterology, Guangzhou 510655, China; Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou 510655, China; Department of Immunobiology, School of Medicine, Yale University, CT, USA.
Abstract:
Uncertainty exists regarding the mechanisms by which hypoxia-inducible factors (HIFs) control CD8+T-cell migration into tumor microenvironments. Here, we found that HIF-1α knockdown or overexpression resulted in increased or decreased CXCL9, -10, and -11 expression in vitro, respectively. Gene Set Variation Analysis revealed that elevated HIF-1α levels correlated with a poor prognosis, severe pathological stage, and an absence of CD8+ T cells in the tumor microenvironment in colorectal cancer (CRC) patients. HIF-1α was inversely associated with pathways beneficial to anti-tumor immunotherapy and cytokine/chemokine function. In vivo, inhibiting HIF-1α or its upstream regulator BIRC2 significantly suppressed tumor growth and promoted CD8+ T-cell infiltration. CXCR3 neutralizing antibodies reversed these effects, implicating the involvement of CXCL9, -10, and -11/CXCR3 axis. The presence of HIF-1α weakened the upregulation of CXCL9, -10, and -11 by bleomycin and doxorubicin. Combining HIF-1α inhibition with bleomycin promoted CD8+ T-cell infiltration and tumor suppression in vivo. Moreover, doxorubicin could upregulate CXCL9, -10 and -11 by suppressing HIF-1α. Our findings highlight the potential of HIF-1α inhibition to improve CRC microenvironments and increase chemotherapy sensitivity.
Insights
Hypoxia-inducible factor-1 alpha (HIF-1α) negatively regulates CD8+ T-cell infiltration in colorectal cancer. Inhibiting HIF-1α enhances anti-tumor immunity and chemotherapy effectiveness.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Hypoxia-inducible factors (HIFs) role in tumor immunity remains unclear.
- CD8+ T-cell infiltration is crucial for anti-tumor responses.
Purpose of the Study:
- Investigate HIF-1α's mechanism in CD8+ T-cell migration within colorectal cancer (CRC) tumor microenvironments.
- Evaluate HIF-1α inhibition as a therapeutic strategy for CRC.
Main Methods:
- In vitro knockdown/overexpression of HIF-1α.
- Gene Set Variation Analysis (GSVA) on patient data.
- In vivo tumor xenograft models.
- CXCR3 neutralizing antibody experiments.
- Chemotherapy (bleomycin, doxorubicin) treatments.
Main Results:
- HIF-1α inversely correlates with CXCL9, -10, -11 expression and CD8+ T-cell infiltration in CRC.
- Elevated HIF-1α is linked to poor prognosis and advanced pathological stages.
- HIF-1α inhibition or BIRC2 suppression reduced tumor growth and increased CD8+ T-cell infiltration.
- The CXCL9, -10, -11/CXCR3 axis is critical for HIF-1α-mediated T-cell migration.
- HIF-1α inhibition potentiated chemotherapy efficacy.
Conclusions:
- HIF-1α acts as a negative regulator of anti-tumor CD8+ T-cell infiltration in CRC.
- Targeting HIF-1α can reprogram the tumor microenvironment to enhance anti-tumor immunity.
- HIF-1α inhibition represents a promising strategy to improve immunotherapy and chemotherapy sensitivity in CRC.
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