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Background Transarterial chemoembolisation (TACE) is a standard first-line therapy for intermediate-to-advanced hepatocellular carcinoma (HCC), aiming to reduce tumor burden and prolong survival. However, its long-term efficacy is significantly constrained by frequent tumor recurrence and therapeutic resistance driven by treatment-induced immune evasion. This study aims to elucidate the underlying resistance mechanisms by comprehensively mapping the topological remodeling of the tumor microenvironment (TME) following TACE.Methods We applied an integrative spatial multi-omics strategy, combining bulk RNA sequencing (RNA-seq), single-cell RNA sequencing (scRNA-seq), spatial transcriptomics at subcellular-resolution, and spatial proteomics. We analyzed primary treatment-naïve tumors and surgically resected specimens from patients who underwent TACE, alongside extensive public clinical cohorts. Machine learning models and spatial niche analyses were employed to identify functional cell states and predictive biomarkers for treatment response.Results We found that TACE creates a profoundly hypoxic microenvironment within the tumor core ( IDDF2026-ABS-0170 Figure 1(A)), which selectively drives the enrichment of a pro-fibrotic tumor-associated macrophage (TAM) population characterized by high expression of SPP1 and FN1 (SPP1+ TAMs) (IDDF2026-ABS-0170 Figure 1(B)). Machine learning identified these SPP1+ TAMs as top predictors of TACE non-response and poor patient prognosis (IDDF2026-ABS-0170 Figure 1(C)). Spatial mapping demonstrated that SPP1+ macrophages remodel the extracellular matrix (ECM) to establish fibrotic niches (IDDF2026-ABS-0170 Figure 1(D)). Furthermore, they restrict CD8+ T cell infiltration and activation, strengthening immunosuppressive cell-cell interactions via the FN1-CD44 axis (IDDF2026-ABS-0170 Figure 1(E)), thereby orchestrating profound immune exclusion and facilitating post-TACE resistance (IDDF2026-ABS-0170 Figure 1(F)).Conclusions Our study uncovers a hypoxia-induced, macrophage-driven fibrotic program as a key determinant of immune evasion following TACE. It highlights that interrupting this fibrotic circuit by combining anti-fibrotic or macrophage-targeted interventions with immunotherapy represents a promising therapeutic avenue to overcome resistance and improve clinical outcomes in HCC.Abstract IDDF2026-ABS-0170 Figure 1