2. Academic Validation
  3. Galectin-4 drives anti-PD-L1/BVZ resistance by regulating metabolic adaptation and tumour-associated neutrophils in hepatocellular carcinoma

Galectin-4 drives anti-PD-L1/BVZ resistance by regulating metabolic adaptation and tumour-associated neutrophils in hepatocellular carcinoma

  • Gut. 2025 Oct 7:gutjnl-2025-336374. doi: 10.1136/gutjnl-2025-336374.
Wenxin Xu 1,  Yufei Zhao 1,  Jialei Weng 2,  Mincheng Yu 1,  Qiang Yu 1,  Peiyi Xie 1,  Shaoqing Liu 3,  Lei Guo 1,  Bo Zhang 1,  Yongfeng Xu 1,  Yongsheng Xiao 1,  Huichuan Sun 4,  Qinghai Ye 4,  Hui Li 4 5
Affiliations

Affiliations

  • 1 Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital Fudan University, Shanghai, Shanghai, China.
  • 2 Department of Surgical Oncology, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, Zhejiang, China.
  • 3 Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • 4 Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital Fudan University, Shanghai, Shanghai, China li.hui1@zs-hospital.sh.cn ye.qinghai@zs-hospital.sh.cn sun.huichuan@zs-hospital.sh.cn.
  • 5 Department of Liver Surgery, Zhongshan Hospital Fudan University Xiamen Branch, Xiamen, Fujian, China.
PMID: 41057233 DOI: 10.1136/gutjnl-2025-336374
Abstract

Background: The combination of atezolizumab and bevacizumab (ATZ/BVZ) therapy has significantly advanced therapeutic approaches for hepatocellular carcinoma (HCC). However, less than 30% of patients achieve durable responses, highlighting the urgent need to understand mechanisms underlying resistance.

Objective: This study aimed to elucidate the mechanisms of resistance to ATZ/BVZ therapy in HCC and identify druggable targets associated with resistance, thus improving the treatment efficacy of ATZ/BVZ-resistant HCC.

Design: We employed single-cell RNA Sequencing and a prospective clinical cohort (NCT04649489) to identify and characterise potential genes that contribute to ATZ/BVZ therapy resistance. Multiple preclinical HCC models and a coculture system were constructed, and cytometry by time-of-flight technology was used to further explore the relevant molecular mechanism.

Results: Elevated baseline serum Galectin-4 levels correlated with resistance to ATZ/BVZ therapy and unfavourable prognosis in HCC. Galectin-4 overexpression nullified ATZ/BVZ therapy efficacy through promoting metabolic adaptation and fostering an immunosuppressive tumour microenvironment characterised by reduced infiltration and impaired cytotoxicity of CD8+ T cells and accumulation of PD-L1+ tumour-associated neutrophils. Mechanistically, Galectin-4 inhibited proteasomal degradation of Lactate Dehydrogenase A (LDHA) by competitively decreasing tripartite motif containing 28 binding, thereby enhancing glycolysis and amplifying HIF-1α-mediated C-X-C motif chemokine ligand 6 (CXCL6) expression. Genetic knockdown or pharmacological inhibition of Galectin-4 reversed metabolic adaptation and immune exclusion, and restored sensitivity to anti-PD-L1/BVZ therapy in preclinical models.

Conclusion: Activation of the Galectin-4/LDHA/HIF-1α and CXCL6 axis plays a pivotal role in ATZ/BVZ therapy resistance. Galectin-4 serves as a promising therapeutic target to improve immunotherapy efficacy and an effective predictive biomarker for immunotherapy response in HCC.

Keywords

Drug resistance; Hepatocellular carcinoma; Immunotherapy.

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