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Background Hepatocellular carcinoma (HCC) accounts for over 90% of all primary liver cancers and is frequently unresectable at diagnosis. Neoadjuvant strategies aimed at downsizing tumors may enable curative resection in these patients. Our institution previously completed a clinical trial combining the VEGF receptor tyrosine kinase inhibitor cabozantinib and the anti-PD-L1 immune checkpoint inhibitor nivolumab in patients with unresectable HCC ( NCT03299946). Major pathological responses were observed in 5 of 12 patients (42%), with enrichment of effector T cells and tertiary lymphoid structures in post-treatment tumor samples. However, the impact of this neoadjuvant regimen on cancer-associated fibroblast (CAF) populations, and their relationship to treatment response, remains poorly understood.Methods We performed spatial profiling of tumor samples from trial participants stratified by pathologic response using 10X Genomics Visium spatial transcriptomics to examine CAF presence and phenotype across tumors. We similarly selected regions of interest at the tumor-stromal interface and within the tumor interior to apply a novel 38-marker imaging mass cytometry (IMC) panel emphasizing CAF phenotypes and functional markers.Results Spatial transcriptomic analysis revealed that tumors from responders were enriched in CAFs expressing antigen presentation-related genes, including HLA-B and CD74, characteristic of antigen-presenting CAFs (apCAFs). Gene set enrichment analysis demonstrated upregulation of immunomodulatory pathways such as TNFa signaling, interferon gamma response, and inflammatory response in the CAFs of responders. IMC confirmed a significantly higher proportion of apCAFs in tumors from responders compared to non-responders. Furthermore, apCAFs were found in closer spatial proximity to T cells in the tumors of responders, suggesting a potential role in modulating antitumor immunity via local antigen presentation.Conclusions Response to neoadjuvant cabozantinib and nivolumab treatment in HCC is associated with antigen-presenting CAFs spatially localized near T cells in tumors. Subsequent analyses will further define the specific T cell populations near apCAFs. These findings suggest that fibroblast-mediated antigen presentation may contribute to effective antitumor immune responses in the neoadjuvant setting. Ongoing studies aim to further dissect the functional role of CAF subsets in shaping immune responses and therapeutic outcomes in HCC.Acknowledgements This work was supported by imCORE Grant 142583 to Johns HopkinsEthics Approval The protocol was approved by the Institutional Review Board (IRB), All patients provided written informed consent prior to enrollment.