Integrated Single-Cell and Spatial Transcriptomics Analyses Delineate a <i>BAG3</i>-Associated Macrophage Program with Microenvironmental and Prognostic Relevance in Hepatocellular Carcinoma

<b>Background:</b> Tumor-associated macrophages (TAMs) are key components of the hepatocellular carcinoma (HCC) microenvironment, but their spatial heterogeneity remains incompletely characterized. We aimed to assess the biological and prognostic relevance of a <i>BAG3</i>-associated TAM program in HCC. <b>Methods:</b> Public single-cell RNA sequencing (scRNA-seq) datasets were analyzed to characterize TAM heterogeneity, and an integrated validation scRNA-seq dataset was used to assess reproducibility. Spatial transcriptomics was used to provide spatial context in a small treatment-exposed cohort. Pseudotime, regulatory network, and cell-cell communication analyses were performed to characterize state transitions and microenvironmental interactions. Survival modeling evaluated the prognostic relevance of the <i>BAG3</i>-associated program. <b>Results:</b> Five TAM subsets were identified, including MARCO⁺, MT⁺ RTM-, MMP9⁺, UBE2C⁺, and BAG3⁺ TAMs. Among them, BAG3⁺ TAMs, a less well-characterized subset, exhibited coordinated stress-adaptive, proteostasis-related, and matrix-remodeling programs that were reproduced in the validation dataset. Pseudotime analysis suggested a continuum of TAM states, with BAG3⁺ TAM stress-remodeling features enriched toward late pseudotime. Communication analysis centered on BAG3⁺ TAMs suggested crosstalk between inflammatory stress cues and angiogenic, stromal-remodeling, and immunomodulatory programs; this pattern was primarily supported by HBV-derived samples and recurrently involved the MIF-CD74 axis. Spatial mapping further supported BAG3⁺ TAM-enriched niches with elevated AP-1, EGR1, and NFKB1 activity. A <i>BAG3</i>-associated risk score derived from a 10-gene signature remained an independent prognostic factor for overall survival after clinical adjustment. <b>Conclusions:</b> These findings characterize a <i>BAG3</i>-associated TAM program with spatial, immunoregulatory, and prognostic relevance in HCC, and support its further evaluation in biomarker and mechanistic studies.