Single-Cell Transcriptomic Profiling Reveals That Macrophage-Induced Angiogenesis Contributes to Immunotherapy Resistance in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) ranks among the top causes of cancer-related mortality worldwide, and its complex tumor microenvironment (TME) contributes to poor responses to immunotherapy. Although PD-1/PD-L1 blockade has emerged as an effective treatment strategy, therapeutic resistance frequently limits its clinical benefit. Here, we uncover a distinct macrophage population associated with anti-PD-1 resistance in HCC. Single-cell transcriptomic profiling reveals an <i>NFKBIZ</i>⁺ M0 macrophage subset predominantly present in non-responders. Notably, these macrophages exhibit a hypoxia-induced phenotype characterized by the secretion of <i>VEGFA</i> and <i>HBEGF</i>, which cooperatively enhance tumor angiogenesis, alongside an elevated expression of the inflammatory chemokines <i>CXCL2</i>, <i>CXCL3</i>, and <i>CXCL8</i> that consolidate an immunosuppressive, pro-tumorigenic microenvironment. Transcriptional regulatory network analysis further identified <i>FOSB</i>-<i>VEGFA</i> and <i>FOS</i>-<i>HBEGF</i> axes as key drivers of this pathogenic macrophage phenotype. Our findings define a distinct <i>NFKBIZ</i>⁺ macrophage population that mechanistically links hypoxia, angiogenesis, and immune evasion to PD-1 blockade resistance. This work provides new insights into the cellular and molecular basis of immunotherapy failure in HCC and highlights potential targets for overcoming treatment resistance.