Postn⁺ cancer-associated fibroblasts (CAFs) determine the efficacy of immunotherapy in hepatocellular carcinoma (HCC). This study investigated the role of CAF subsets in the tumor microenvironment (TME) and their impact on immunotherapy response in HCC patients. Using single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and multiplex immunofluorescence, the researchers identified six CAF subtypes in HCC tumors, including POSTN⁺ CAFs. POSTN⁺ CAFs were found to be a significant barrier to effective T-cell infiltration and immunotherapy response. They interact with SPP1⁺ macrophages via the IL-6/STAT3 signaling pathway, promoting an immunosuppressive TME. Patients with high levels of both POSTN⁺ CAFs and SPP1⁺ macrophages showed reduced therapeutic benefit. The study highlights the importance of targeting POSTN⁺ CAFs to improve immunotherapy outcomes in HCC. The findings suggest that POSTN⁺ CAFs play a critical role in immunotherapy resistance by promoting an immunosuppressive TME and hindering T-cell infiltration. The study also reveals the complex interactions between CAFs, HCC cells, and immune cells, which may provide new targets for CAF-targeted therapy. The results emphasize the potential of targeting specific CAF subpopulations to enhance the effectiveness of immunotherapy in HCC.Postn⁺ cancer-associated fibroblasts (CAFs) determine the efficacy of immunotherapy in hepatocellular carcinoma (HCC). This study investigated the role of CAF subsets in the tumor microenvironment (TME) and their impact on immunotherapy response in HCC patients. Using single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and multiplex immunofluorescence, the researchers identified six CAF subtypes in HCC tumors, including POSTN⁺ CAFs. POSTN⁺ CAFs were found to be a significant barrier to effective T-cell infiltration and immunotherapy response. They interact with SPP1⁺ macrophages via the IL-6/STAT3 signaling pathway, promoting an immunosuppressive TME. Patients with high levels of both POSTN⁺ CAFs and SPP1⁺ macrophages showed reduced therapeutic benefit. The study highlights the importance of targeting POSTN⁺ CAFs to improve immunotherapy outcomes in HCC. The findings suggest that POSTN⁺ CAFs play a critical role in immunotherapy resistance by promoting an immunosuppressive TME and hindering T-cell infiltration. The study also reveals the complex interactions between CAFs, HCC cells, and immune cells, which may provide new targets for CAF-targeted therapy. The results emphasize the potential of targeting specific CAF subpopulations to enhance the effectiveness of immunotherapy in HCC.