Cancer-associated fibroblasts (CAFs) are the main components in the tumor microenvironment. Tumors activate fibroblasts from quiescent state into activated state by secreting cytokines, and activated CAFs may in turn promote tumor progression and metastasis. Therefore, studies targeting CAFs could enrich the therapeutic options for tumor treatment. In this study, we demonstrate that the content of lipid droplets and the expression of autophagosomes were higher in CAFs than in peri-tumor fibroblasts (PTFs), which was inhibited by 5-(tetradecyloxy)-2-furoic acid(TOFA). The expression of CD36 in CAFs was higher than that in PTFs at both mRNA and protein levels. Inhibition of CD36 activity using either the CD36 inhibitor SSO or siRNA had a significant negative impact on the proliferation and migration abilities of CAFs, which was associated with reduced levels of relevant activated genes (α-SMA, FAP, Vimentin) and cytokines (IL-6, TGF-β and VEGF-α). SSO also inhibited HCC growth and tumorigenesis in nude mice orthotopically implanted with CAFs and HCC cells. Our data further show that CD36⁺CAFs affected the expression of PD-1 in CTLs leading to CTL exhaustion, and that patients with high CD36 expression in CAFs were correlated with shorter overall survival (OS). Together, our data demonstrate that CAFs were active in lipid metabolism with increased lipid content and lipophagy activity. CD36 may play a key role in the regulation of the biological behaviors of CAFs, which may influence the proliferation and migration of tumor cells by reprograming the lipid metabolism in tumor cells. Thus, CD36 could be an effective therapeutic target for the treatment of HCC.

癌症相关成纤维细胞（CAF）是肿瘤微环境的主要成分。肿瘤通过分泌细胞因子将成纤维细胞从静止状态激活为激活状态，而激活的CAF可能反过来促进肿瘤的进展和转移。因此，针对 CAF 的研究可以丰富肿瘤治疗的选择。在本研究中，我们证明 CAF 中脂滴的含量和自噬体的表达高于肿瘤周围成纤维细胞 (PTF)，而肿瘤周围成纤维细胞 (PTF) 受到 5-(十四烷氧基)-2-糠酸 (TOFA) 的抑制。 CD36在CAF中的mRNA和蛋白水平表达均高于PTF。使用 CD36 抑制剂 SSO 或 siRNA 抑制 CD36 活性对 CAF 的增殖和迁移能力产生显着的负面影响，这与相关激活基因（α-SMA、FAP、Vimentin）和细胞因子（IL- 6、TGF-β和VEGF-α）。 SSO 还抑制原位植入 CAF 和 HCC 细胞的裸鼠的 HCC 生长和肿瘤发生。我们的数据进一步表明，CD36 ⁺CAF 影响 CTL 中 PD-1 的表达，导致 CTL 耗竭，并且 CAF 中 CD36 高表达的患者与较短的总生存期 (OS) 相关。总之，我们的数据表明，CAF 在脂质代谢中具有活性，脂质含量和自噬活性增加。 CD36可能在CAF生物学行为的调节中发挥关键作用，可能通过重编程肿瘤细胞内的脂质代谢来影响肿瘤细胞的增殖和迁移。因此，CD36可能成为治疗HCC的有效治疗靶点。