Background: For most colorectal cancer (CRC) patients, expanding the benefits of immunotherapy, particularly through blocking programmed cell death-1 (PD-1) and its ligand (PD-L1), is crucial, especially in cases with limited response to neoadjuvant therapy. This study investigates the role of Myoferlin (MYOF) as a novel target in CRC immunotherapy. Methods: Human CRC cell lines (RKO, HCT116), normal intestinal epithelial cells (HIEC-6), and the murine CRC cell line MC38 were used to study the effects of apatinib and MYOF in CRC cells. RNA sequencing, the CPTAC and TCGA databases, and other molecular and cellular methods were applied to disclose the mechanisms involved. A series of mouse models were established to assess the effects of apatinib and MYOF knockdown on tumor progression, immune cell infiltration, and immune checkpoint protein response. Results: We found that MYOF is overexpressed in CRC and linked to immune cell infiltration and checkpoint expression. Suppression of MYOF expression significantly inhibited CRC cell proliferation and migration, as well as reduced PD-L1 protein levels. Integrative analysis showed that apatinib modulates MYOF expression via VEGFR2, resulting in decreased PD-L1 expression, increased CD8+ T cell infiltration, and reduced pro-tumor M2 macrophages. Animal experiments further revealed that apatinib treatment or MYOF knockdown enhanced the efficacy of immune checkpoint blockade (ICB) in CRC. Conclusions: These findings highlight novel antitumor mechanisms of MYOF and suggest that combining apatinib with ICB therapy may improve CRC treatment outcomes, offering a promising strategy to enhance immune responses.
背景：对于大多数结直肠癌患者而言，扩大免疫治疗的获益至关重要，特别是在新辅助治疗反应有限的情况下，通过阻断程序性细胞死亡蛋白-1及其配体的治疗策略尤为重要。本研究旨在探讨肌脂蛋白作为结直肠癌免疫治疗新靶点的作用机制。方法：采用人源结直肠癌细胞系、正常肠上皮细胞及小鼠结直肠癌细胞系，通过RNA测序、临床蛋白质组学数据库及多种分子细胞学技术，系统研究阿帕替尼与肌脂蛋白在结直肠癌细胞中的作用机制。建立系列小鼠模型评估阿帕替尼干预及肌脂蛋白敲低对肿瘤进展、免疫细胞浸润及免疫检查点蛋白应答的影响。结果：研究发现肌脂蛋白在结直肠癌中过表达，且与免疫细胞浸润及检查点表达相关。抑制肌脂蛋白表达可显著降低结直肠癌细胞增殖迁移能力，并下调程序性死亡配体-1蛋白水平。整合分析显示阿帕替尼通过血管内皮生长因子受体2调控肌脂蛋白表达，进而降低程序性死亡配体-1表达水平，促进CD8+ T细胞浸润，同时减少促肿瘤M2型巨噬细胞。动物实验进一步证实阿帕替尼治疗或肌脂蛋白敲低能增强免疫检查点阻断疗法在结直肠癌中的疗效。结论：本研究揭示了肌脂蛋白抗肿瘤的新机制，表明阿帕替尼联合免疫检查点阻断疗法可能改善结直肠癌治疗效果，为增强免疫应答提供了具有前景的治疗策略。
肿瘤(癌症)患者之家