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

作者：Wenxin Xu, Yufei Zhao, Jialei Weng, Mincheng Yu, Qiang Yu, Peiyi Xie, Shaoqing Liu, Lei Guo, Bo Zhang, Yongfeng Xu, Yong‐Sheng Xiao, Hui‐Chuan Sun, Qing‐Hai Ye, Hui Li · 发表于：Gut · 年份：2025 · DOI：10.1136/gutjnl-2025-336374 · 被引用次数：10 · 研究领域：Galectins and Cancer Biology、Ferroptosis and cancer prognosis、Glycosylation and Glycoproteins Research

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 gl...