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
  • 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 [email protected] [email protected] [email protected].
  • 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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