Despite the notable achievements of programmed death 1 (PD-1) antibodies in treating various cancers, the overall efficacy remains limited in the majority of colorectal cancer (CRC) cases. Metabolism reprogramming of tumors inhibits the tricarboxylic acid (TCA) cycle, leading to down-regulation of fumarate hydratase (FH), which is related to poor prognosis in CRC patients. By establishing a tumor-bearing mouse model of CRC with Fh1 expression deficiency, we confirmed that the therapeutic effect of PD-1 antibodies alone was suboptimal in mice with low Fh1 expression, which was improved by combination with a protein invertase subtilisin/kexin 9 (PCSK9) inhibitor. Mechanistically, FH binds to Ras-related nucleoprotein (RAN), which inhibits the nuclear import of the PCSK9 transcription factor SREBF1/2, thus reducing the expression of PCSK9. This leads to increased clonal expansion of CD8+ T cells while the number of Tregs remains unchanged, and the expression of PD-L1 does not change significantly, thus enhancing the immunotherapy response. On the contrary, the expression of PCSK9 increased in CRC cells with low FH expression, which antagonized the effects of immunotherapy. Overall, CRC patients with low FH expression may benefit from combinatorial therapy with PD-1 antibodies and PCSK9 inhibitors to enhance the curative effect.
尽管程序性死亡受体1（PD-1）抗体在多种癌症治疗中取得显著成效，但其在大多数结直肠癌（CRC）病例中的总体疗效仍有限。肿瘤代谢重编程抑制三羧酸（TCA）循环，导致延胡索酸水合酶（FH）表达下调，这与CRC患者的不良预后相关。通过建立Fh1表达缺陷的CRC荷瘤小鼠模型，我们证实单独使用PD-1抗体对低Fh1表达小鼠的治疗效果欠佳，而联合使用蛋白转化酶枯草溶菌素9（PCSK9）抑制剂可改善疗效。机制上，FH与Ras相关核蛋白（RAN）结合，抑制PCSK9转录因子SREBF1/2的核输入，从而降低PCSK9表达。这导致CD8+ T细胞克隆扩增增加，而Tregs数量保持不变，且PD-L1表达未发生显著变化，从而增强免疫治疗反应。相反，低FH表达的CRC细胞中PCSK9表达升高，拮抗了免疫治疗的效果。总体而言，低FH表达的CRC患者可能受益于PD-1抗体与PCSK9抑制剂的联合治疗以增强疗效。
肿瘤(癌症)患者之家