Background:Hepatocellular carcinoma (HCC) is among the deadliest cancers worldwide, and advanced HCC is difficult to treat. Identifying specific cell subpopulations in the tumor microenvironment and exploring interactions between the cells and their environment are crucial for understanding the development, prognosis, and treatment of tumors.Methods:In this study, we constructed a tumor ecological landscape of 14 patients with HCC from 43 tumor tissue samples and 14 adjacent control samples. We used bioinformatics analysis to reveal cell subpopulations with potentially specific functions in the tumor microenvironment and to explore the interactions between tumor cells and the tumor microenvironment.Results:Immune cell infiltration was evident in the tumor tissues, andBTG1+RGS1+central memory T cells (Tcms) interact with tumor cells throughCCL5-SDC4/1axis. HSPA1B may be associated with remodeling of the tumor ecological niche in HCC. Cancer-associated fibroblasts (CAFs) and macrophages (TAMs) were closely associated with tumor cells.APOC1+SPP1+TAM secretes SPP1, which binds to ITGF1 secreted by CAFs to remodel the tumor microenvironment. More interestingly,FAP+CAF interacts with naïve T cells via theCXCL12–CXCR4axis, which may lead to resistance to immune checkpoint inhibitor therapy.Conclusion:Our study suggests the presence of tumor cells with drug-resistant potential in the HCC microenvironment. Among non-tumor cells, highNDUFA4L2expression in fibroblasts may promote tumor progression, while highHSPA1Bexpression in central memory T cells may exert anti-tumor effects. In addition, theCCL5–SDC4/1interaction betweenBTG1+RGS1+Tcms and tumor cells may promote tumor progression. Focusing on the roles of CAFs and TAMs, which are closely related to tumor cells, in tumors would be beneficial to the progress of systemic therapy research.