间皮素 (MSLN) 蛋白的表达在包括结直肠癌 (CRC) 在内的多种恶性肿瘤中存在很大差异，高水平的表达与侵袭性临床病理特征和较差的患者生存率相关。结直肠癌是一种常见且致命的癌症。是癌症相关死亡的第三大常见原因和第二大常见原因。虽然全身治疗仍然是大多数 IV 期（转移性；m）CRC 患者的主要治疗选择，但他们的疾病最终变得难治，85% 在 5 年内死亡。微卫星稳定 (MSS) CRC 肿瘤占 mCRC 患者的 90% 以上，通常对免疫治疗干预无效。在我们目前的工作中，我们表征了 CRC 中的 MSLN 水平，特别是将表达与相关 CRC 亚型的临床结果相关联，并探讨 MSLN 表达如何影响瘤周微环境中免疫激活和抑制的状态。较高的 MSLN 表达在 CMS1 和 CMS4 CRC 亚型中普遍存在，并且与患者群体中较高的基因突变率相关。此外，MSLN 高的患者表现出 M1/M2 巨噬细胞浸润增加、PD-L1 染色增加、免疫抑制基因表达增加、炎症、TGF-β、IL6/JAK/STAT3、IL2/STAT5 信号通路富集以及 KRAS 和FBXW7。总之，这些结果表明 MSLN 蛋白是抗原特异性治疗的潜在靶点，并支持对其致瘤效应的研究，以确定对 MSLN 高表达 MSS CRC 患者可能的治疗干预措施。© 2024。作者。

The expression of the protein Mesothelin (MSLN) is highly variable in several malignancies, including colorectal cancer (CRC), and high levels are associated with aggressive clinicopathological features and worse patient survival. Colorectal cancer is both a common and deadly cancer; being the third most common in incidence and second most common cause of cancer-related death. While systemic therapy remains the primary therapeutic option for most patients with stage IV (metastatic; m) CRC, their disease eventually becomes treatment refractory, and 85% succumb within 5 years. Microsatellite-stable (MSS) CRC tumors, which constitute more than 90% of patients with mCRC, are generally refractory to immunotherapeutic interventions. In our current work, we characterize MSLN levels in CRC, specifically correlating expression with clinical outcomes in relevant CRC subtypes, and explore how MSLN expression impacts the status of immune activation and suppression in the peritumoral microenvironment. Higher MSLN expression is prevalent in CMS1 and CMS4 CRC subtypes and correlates with higher gene mutation rates across the patient cohorts. Further, MSLN-high patients exhibit increased M1/M2 macrophage infiltration, PD-L1 staining, immune-inhibitory gene expression, enrichment in inflammatory, TGF-β, IL6/JAK/STAT3, IL2/STAT5 signaling pathways, and mutation in KRAS and FBXW7. Together, these results suggest that MSLN protein is a potential target for antigen-specific therapy and supports investigation into its tumorigenic effects to identify possible therapeutic interventions for patients with high MSLN expressing MSS CRC.© 2024. The Author(s).