Hepatocellular carcinoma (HCC) is an immunotherapy-resistant malignancy characterized by high cellular heterogeneity. The diversity of cell types and the interplay between tumor and non-tumor cells remain to be clarified. Single cell RNA sequencing of human and mouse HCC tumors revealed heterogeneity of cancer-associated fibroblast (CAF). Cross-species analysis determined the prominent CD36⁺ CAFs exhibited high-level lipid metabolism and expression of macrophage migration inhibitory factor (MIF). Lineage-tracing assays showed CD36⁺CAFs were derived from hepatic stellate cells. Furthermore, CD36 mediated oxidized LDL uptake-dependent MIF expression via lipid peroxidation/p38/CEBPs axis in CD36⁺ CAFs, which recruited CD33⁺myeloid-derived suppressor cells (MDSCs) in MIF- and CD74-dependent manner. Co-implantation of CD36⁺ CAFs with HCC cells promotes HCC progression in vivo. Finally, CD36 inhibitor synergizes with anti-PD-1 immunotherapy by restoring antitumor T-cell responses in HCC. Our work underscores the importance of elucidating the function of specific CAF subset in understanding the interplay between the tumor microenvironment and immune system.

肝细胞癌 (HCC) 是一种免疫治疗耐药的恶性肿瘤，其特征在于高度的细胞异质性。细胞类型的多样性以及肿瘤和非肿瘤细胞之间的相互作用仍有待阐明。人类和小鼠 HCC 肿瘤的单细胞 RNA 测序揭示了癌症相关成纤维细胞 (CAF) 的异质性。跨物种分析确定突出的 CD36 ⁺ CAF 表现出高水平的脂质代谢和巨噬细胞迁移抑制因子 (MIF) 的表达。谱系追踪分析显示 CD36 ⁺ CAF 来源于肝星状细胞。此外，CD36 在 CD36 ⁺ CAF 中通过脂质过氧化/p38/CEBPs 轴介导氧化 LDL 摄取依赖性 MIF 表达，其募集 CD33 ⁺MIF 和 CD74 依赖性方式的髓源性抑制细胞 (MDSC)。^{CD36 +} CAF 与 HCC 细胞共同植入可促进体内 HCC 进展。最后，CD36 抑制剂通过恢复 HCC 中的抗肿瘤 T 细胞反应与抗 PD-1 免疫疗法协同作用。我们的工作强调了阐明特定 CAF 子集的功能对于理解肿瘤微环境与免疫系统之间的相互作用的重要性。