This study investigates the role of cancer-associated fibroblasts (CAFs) in the efficacy of immunotherapy for hepatocellular carcinoma (HCC). By compiling single-cell RNA sequencing (scRNA-seq) datasets from six datasets, an HCC atlas was generated, identifying six CAF subtypes: CD36+, CXCL12+, MYH11+, SEPT7+, POSTN+, and STMN1+. POSTN+ CAFs were found to be crucial in promoting HCC progression by hindering T-cell infiltration and reducing the effectiveness of immunotherapy. The study also revealed that POSTN+ CAFs interact with SPP1+ macrophages via the IL-6/STAT3 signaling pathway, contributing to an immunosuppressive microenvironment. Patients with elevated levels of both POSTN+ CAFs and SPP1+ macrophages showed less therapeutic benefit from immunotherapy. The findings highlight the potential of targeting specific CAF subpopulations to improve clinical responses to immunotherapy in HCC.This study investigates the role of cancer-associated fibroblasts (CAFs) in the efficacy of immunotherapy for hepatocellular carcinoma (HCC). By compiling single-cell RNA sequencing (scRNA-seq) datasets from six datasets, an HCC atlas was generated, identifying six CAF subtypes: CD36+, CXCL12+, MYH11+, SEPT7+, POSTN+, and STMN1+. POSTN+ CAFs were found to be crucial in promoting HCC progression by hindering T-cell infiltration and reducing the effectiveness of immunotherapy. The study also revealed that POSTN+ CAFs interact with SPP1+ macrophages via the IL-6/STAT3 signaling pathway, contributing to an immunosuppressive microenvironment. Patients with elevated levels of both POSTN+ CAFs and SPP1+ macrophages showed less therapeutic benefit from immunotherapy. The findings highlight the potential of targeting specific CAF subpopulations to improve clinical responses to immunotherapy in HCC.