Jabbarzadeh Kaboli Parham, Roozitalab Ghazaal, Farghadani Reyhaneh, Eskandarian Zoya, Zerrouqi Abdessamad
Department of Biochemistry, Faculty of Medicine, Medical University of Warsaw, Warsaw, Poland.
Noncommunicable Diseases Research Center, Fasa University of Medical Sciences, Fasa, Iran.
Front Immunol. 2024 Nov 27;15:1498391. doi: 10.3389/fimmu.2024.1498391. eCollection 2024.
Cellular mesenchymal-epithelial transition factor (c-MET), also known as hepatocyte growth factor receptor (HGFR), is a crucial receptor tyrosine kinase implicated in various solid tumors, including lung, breast, and liver cancers. The concomitant expression of c-MET and PD-L1 in tumors, such as hepatocellular carcinoma, highlights their prognostic significance and connection to therapeutic resistance. Cancer-associated fibroblasts and mesenchymal stromal cells produce hepatocyte growth factor (HGF), activating c-MET signaling in tumor cells and myeloid-derived suppressor cells (MDSC). This activation leads to metabolic reprogramming and increased activity of enzymes like glutaminase (GLS), indoleamine 2,3-dioxygenase (IDO), and arginase 1 (ARG1), depleting essential amino acids in the tumor microenvironment that are vital for effector immune cell function. This review highlights the interplay between tumor cells and myeloid-derived suppressor cells (MDSCs) that create an immunosuppressive environment while providing targets for c-MET-focused immunotherapy. It emphasizes the clinical implications of c-MET inhibition on the behavior of immune cells such as neutrophils, macrophages, T cells, and NK cells. It explores the potential of c-MET antagonism combined with immunotherapeutic strategies to enhance cancer treatment paradigms. This review also discusses the innovative cancer immunotherapies targeting c-MET, including chimeric antigen receptor (CAR) therapies, monoclonal antibodies, and antibody-drug conjugates, while encouraging the development of a comprehensive strategy that simultaneously tackles immune evasion and enhances anti-tumor efficacy further to improve the clinical prognoses for patients with c-MET-positive malignancies. Despite the challenges and variability in efficacy across different cancer subtypes, continued research into the molecular mechanisms and the development of innovative therapeutic strategies will be crucial.
细胞间充质-上皮转化因子（c-MET），也被称为肝细胞生长因子受体（HGFR），是一种关键的受体酪氨酸激酶，与包括肺癌、乳腺癌和肝癌在内的多种实体瘤有关。在肿瘤（如肝细胞癌）中，c-MET和PD-L1的同时表达凸显了它们的预后意义以及与治疗耐药性的关联。癌症相关成纤维细胞和间充质基质细胞产生肝细胞生长因子（HGF），激活肿瘤细胞和髓系来源抑制细胞（MDSC）中的c-MET信号。这种激活导致代谢重编程以及谷氨酰胺酶（GLS）、吲哚胺2,3-双加氧酶（IDO）和精氨酸酶1（ARG1）等酶的活性增加，耗尽肿瘤微环境中对效应免疫细胞功能至关重要的必需氨基酸。本综述强调了肿瘤细胞与髓系来源抑制细胞（MDSC）之间的相互作用，这种相互作用创造了一种免疫抑制环境，同时为以c-MET为靶点聚焦的免疫治疗提供了靶点。它强调了c-MET抑制对中性粒细胞、巨噬细胞、T细胞和NK细胞等免疫细胞行为的临床意义。它探讨了c-MET拮抗与免疫治疗策略相结合以增强癌症治疗模式的潜力。本综述还讨论了针对c-MET的创新癌症免疫疗法，包括嵌合抗原受体（CAR）疗法、单克隆抗体和抗体-药物偶联物，同时鼓励制定一种全面策略，该策略既能同时应对免疫逃逸又能进一步增强抗肿瘤疗效，以改善c-MET阳性恶性肿瘤患者的临床预后。尽管在不同癌症亚型中存在挑战和疗效差异，但对分子机制的持续研究和创新治疗策略的开发将至关重要。
