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Abstract
Background
The therapeutic potential of immune checkpoint blockade (ICB) extends across various cancers; however, its effectiveness in treating hepatocellular carcinoma (HCC) is frequently curtailed by both inherent and developed resistance.
Objective
This research explored the effectiveness of integrating anlotinib (a broad‐spectrum tyrosine kinase inhibitor) with programmed death‐1 (PD‐1) blockade and offers mechanistic insights into more effective strategies for treating HCC.
Methods
Using patient‐derived organotypic tissue spheroids and orthotopic HCC mouse models, we assessed the effectiveness of anlotinib combined with PD‐1 blockade. The impact on the tumour immune microenvironment and underlying mechanisms were assessed using time‐of‐flight mass cytometry, RNA sequencing, and proteomics across cell lines, mouse models, and HCC patient samples.
Results
The combination of anlotinib with an anti‐PD‐1 antibody enhanced the immune response against HCC in preclinical models. Anlotinib remarkably suppressed the expression of transferrin receptor (TFRC) via the VEGFR2/AKT/HIF‐1α signaling axis. CD8+ T‐cell infiltration into the tumour microenvironment correlated with low expression of TFRC. Anlotinib additionally increased the levels of the chemokine CXCL14, crucial for attracting CD8+ T cells. CXCL14 emerged as a downstream effector of TFRC, exhibiting elevated expression following the silencing of TFRC. Importantly, low TFRC expression was also associated with a better prognosis, enhanced sensitivity to combination therapy, and a favourable response to anti‐PD‐1 therapy in patients with HCC.
Conclusions
Our findings highlight anlotinib's potential to augment the efficacy of anti‐PD‐1 immunotherapy in HCC by targeting TFRC and enhancing CXCL14‐mediated CD8+ T‐cell infiltration. This study contributes to developing novel therapeutic strategies for HCC, emphasizing the role of precision medicine in oncology.
Highlights
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Details

1 Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P. R. China, Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Nantong, P. R. China
2 Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P. R. China
3 Department of Hepatobiliary Surgery, Affiliated Hospital of Nantong University, Nantong, P. R. China
4 Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
5 Department of Liver Surgery & Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, P. R. China, Institutes of Biomedical Sciences, Fudan University, Shanghai, P. R. China