Targeting FGFR1-regulated SPP1 signaling repolarizes immunosuppressive macrophages and sensitizes Hepatocellular
Youhai Jiang1, Jianan Chen2, Zhengyuan Meng3
1Cancer Research Center, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, 230001, Anhui, China; International Cooperation Laboratory on Signal Transduction, National Center for Liver Cancer, Third Affiliated Hospital of Naval Medical University, Shanghai, 200438, China.
Abstract:
The response rate to immune checkpoint blockade (ICB) in hepatocellular carcinoma (HCC) remains unsatisfactory, and the mechanisms of resistance are not fully understood. Here, we investigated the role of fibroblast growth factor receptor 1 (FGFR1) in shaping the tumor microenvironment (TME) and mediating ICB resistance. An anti-PD-1-resistant HCC model was established in mice, followed by single-cell RNA sequencing to profile TME alterations. We observed that ICB resistance was associated with FGFR1 upregulation, which activated MAPK signaling and induced SPP1 expression. This cascade promotes macrophage infiltration and M2-type polarization, while simultaneously suppressing T cell recruitment and cytotoxic function, thereby fostering an immunosuppressive microenvironment. SPP1 knockdown or neutralization significantly reduced macrophage accumulation and restored intratumoral T cell infiltration. Importantly, pharmacological inhibition of FGFR1 using BGJ398 synergized with anti-PD-1 therapy, resulting in enhanced antitumor efficacy in preclinical models. Analysis of clinical datasets further revealed that high FGFR1 expression correlated with poor responses to ICB of HCC patients. Collectively, these findings identify FGFR1 as a key mediator of ICB resistance in HCC. Targeting FGFR1 represents a promising strategy to reprogram the immunosuppressive TME and enhance response to immunotherapy, with potential additional value as a predictive biomarker.
Insights
Fibroblast growth factor receptor 1 (FGFR1) drives resistance to immune checkpoint blockade (ICB) in liver cancer. Targeting FGFR1 may improve immunotherapy response by reprogramming the tumor microenvironment (TME).
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Immune checkpoint blockade (ICB) shows limited efficacy in hepatocellular carcinoma (HCC).
- Mechanisms underlying ICB resistance in HCC are not fully elucidated.
- The tumor microenvironment (TME) plays a critical role in ICB response.
Purpose of the Study:
- To investigate the role of fibroblast growth factor receptor 1 (FGFR1) in mediating ICB resistance in HCC.
- To explore FGFR1's impact on the TME and its potential as a therapeutic target.
Main Methods:
- Establishment of an anti-PD-1-resistant HCC mouse model.
- Single-cell RNA sequencing to analyze TME alterations.
- Pharmacological inhibition of FGFR1 (BGJ398) and anti-PD-1 therapy in preclinical models.
- Analysis of clinical HCC datasets.
Main Results:
- FGFR1 upregulation was associated with ICB resistance, activating MAPK signaling and SPP1 expression.
- This pathway promoted M2-polarized macrophage infiltration and suppressed T cell function, creating an immunosuppressive TME.
- SPP1 inhibition reduced macrophage accumulation and restored T cell infiltration.
- Combined FGFR1 inhibition and anti-PD-1 therapy demonstrated enhanced antitumor effects.
- High FGFR1 expression in HCC patients correlated with poor ICB response.
Conclusions:
- FGFR1 is a key mediator of ICB resistance in HCC by modulating the TME.
- Targeting FGFR1 can reprogram the immunosuppressive TME and enhance immunotherapy efficacy.
- FGFR1 inhibition combined with ICB represents a promising therapeutic strategy for HCC.
- FGFR1 may serve as a predictive biomarker for ICB response in HCC patients.
