结直肠癌是全球癌症相关死亡的主要原因。纤维调节蛋白（FMOD）是主要的蛋白多糖，通过与基质分子结合，对细胞外基质进行重塑，因此在肿瘤生长和转移中发挥重要作用。目前在临床上没有能够针对FMOD治疗结直肠癌的有用药物。在本研究中，我们首先使用公共的全基因组表达数据集来分析FMOD在结直肠癌中的表达水平，并发现FMOD在结直肠癌中上调，并与患者预后不良相关。然后，我们使用Ph.D.-12噬菌体展示肽库获取一个新型的FMOD拮抗肽，命名为RP4，并在体外和体内测试了RP4的抗癌效果。结果显示，RP4通过与FMOD结合，在体内和体外抑制了结直肠癌细胞的生长和转移，同时促进了凋亡。此外，RP4的治疗影响了肿瘤模型中的结直肠癌相关免疫微环境，通过促进细胞毒性CD8+ T细胞和NKT（自然杀伤T细胞），抑制CD25+ Foxp3 + Treg细胞。机制上，RP4通过阻止Akt和Wnt/β-连环蛋白信号通路发挥抗肿瘤作用。该研究暗示FMOD是治疗结直肠癌的潜在靶点，新型FMOD拮抗肽RP4可作为临床用于治疗结直肠癌的药物。

Colorectal cancer (CRC) is the leading cause of cancer-related deaths worldwide. Fibromodulin (FMOD) is the main proteoglycan that contributes to extracellular matrix (ECM) remodeling by binding to matrix molecules, thereby playing an essential role in tumor growth and metastasis. There are still no useful drugs that target FMOD for CRC treatment in clinics. Here, we first used public whole-genome expression datasets to analyze the expression level of FMOD in CRC and found that FMOD was upregulated in CRC and associated with poor patient prognosis. We then used the Ph.D.-12 phage display peptide library to obtain a novel FMOD antagonist peptide, named RP4, and tested its anti-cancer effects of RP4 in vitro and in vivo. These results showed that RP4 inhibited CRC cell growth and metastasis, and promoted apoptosis both in vitro and in vivo by binding to FMOD. In addition, RP4 treatment affected the CRC-associated immune microenvironment in a tumor model by promoting cytotoxic CD8+ T and NKT (natural killer T) cells and inhibiting CD25+ Foxp3+ Treg cells. Mechanistically, RP4 exerted anti-tumor effects by blocking the Akt and Wnt/β-catenin signaling pathways. This study implies that FMOD is a potential target for CRC treatment, and the novel FMOD antagonist peptide RP4 can be developed as a clinical drug for CRC treatment.