ArticleMolecular therapy : the journal of the American Society of Gene Therapy2025
Overcoming immunotherapy resistance in hepatocellular carcinoma by targeting myeloid IL-8/CXCR2 signaling.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed.
- Remodeling the Immune Landscape: How Obesity-Induced SASPs Create a Pro-Tumorigenic Niche.Current obesity reports · 2026Review
- Review
- Interleukin-8 in health and disease.Molecular biomedicine · 2026Review
- Hepatocellular carcinoma metastasis-immune microenvironment crosstalk: emerging mechanisms and immunotherapy.Cellular & molecular biology letters · 2026Review
- Review
- Alternative splicing regulatesiScience · 2026Article
- The value of the serum cytokine-to-immune ratio model in predicting the progression-free survival after interventional therapy for hepatocellular carcinoma.BMC gastroenterology · 2026Article
- Circulating low-density neutrophils as biomarkers of resistance to first-line anti-PD-1/PD-L1 immunotherapy in non-small cell lung cancer.Translational oncology · 2026Article
- IFN-γ induces hematopoietic stem cell myelopoiesis through Meis1 in tumor.Stem cell research & therapy · 2026Article
- Immunotherapy in hepatocellular carcinoma: translating mechanistic insights into clinical advances.Clinical and experimental medicine · 2026Review
- The Molecular Network of Neutrophil Extracellular Traps in Hepatocellular Carcinoma: Biogenesis, Function, and Therapeutic Implications.Molecules (Basel, Switzerland) · 2026Review
- Synergistic Potential of Immune Checkpoint Inhibitor Combined with Neutrophil-Targeted Therapy in Cancer Immunotherapy.Research (Washington, D.C.) · 2026Review
- Unlocking the Power of CXCR2 Inhibition to Overcome Gemcitabine Resistance in Pancreatic Cancer.FASEB bioAdvances · 2026Article
- Myeloid-Derived Suppressor Cells and Radiotherapy: Regulation and Clinical Implications.Journal of Cancer · 2026Review
- Post-translational modification in hepatocellular carcinoma resistance: molecular mechanisms and therapeutic targeting.Frontiers in immunology · 2026Review
- Innate immune signaling-driven myeloid remodeling in cancer: inflammatory amplification, immune suppression, and therapeutic targeting.Frontiers in immunology · 2026Review
- Krüppel-Like Factor 4, a Hub Gate for Cell Crosstalk in Tumor Microenvironment.Cancer medicine · 2026Review
- Neutrophils in the hepatocellular carcinoma microenvironment: orchestrators of progression and immunity.Frontiers in immunology · 2026Review
- A case report of primary hepatoid adenocarcinoma of the vagina and literature review.Frontiers in oncology · 2026Article
- Mechanisms of Immune Checkpoint Inhibitor Resistance in Hepatocellular Carcinoma and Strategies for Reversal.Cancers · 2025Review
Corrections and comments
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Authors and funding
14 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Durable responses to immune checkpoint blockade (ICB) in hepatocellular carcinoma (HCC) are limited to a minority of patients, yet reliable biomarkers are still lacking. Inflammatory cytokines such as interleukin-8 (IL-8) are associated with HCC progression, and IL-8 is known as the chemoattractant for immunosuppressive myeloid cells. Therefore, we aim to elucidate the ICB resistance mechanisms mediated by the activation of the IL-8/CXCR2 pathway. Single-cell RNA sequencing (scRNA-seq) was performed in advanced HCC patients with baseline and on-treatment biopsy after pembrolizumab in a phase 2 clinical trial cohort. Our data revealed that IL-8 and its receptor, CXCR2, mainly derived from immunosuppressive myeloid-derived suppressor cells (MDSCs). In particular, the high circulating IL-8 level was strongly associated with poor ICB response. This myeloid IL-8/CXCR2 pathway was further elucidated in our ICB-resistant orthotopic mouse model using AZD5069, a clinically available CXCR2 antagonist. Suppression of the IL-8/CXCR2 pathway significantly abrogated MDSC trafficking and immunosuppressive activity, which sensitized the anti-PD-L1 blockade to reduce tumor growth and prolong survival. The association between myeloid IL-8 and ICB therapeutic outcomes also extended to multiple cancer types. Collectively, our study not only suggests a potential non-invasive biomarker for patient stratification and monitoring of ICB response but it also provides a proof of concept for combinational immunotherapy to benefit patients who are non-responsive to ICB monotherapy.
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