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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.