Parham Jabbarzadeh Kaboli ^1* Ghazaal Roozitalab ² Reyhaneh Farghadani ³ Zoya Eskandarian ⁴ Abdessamad Zerrouqi ^1*

• ¹ Medical University of Warsaw, Warsaw, Poland
• ² School of Medicine, Fasa University of Medical Sciences, Fasa, Fars, Iran
• ³ Monash University Malaysia, Subang Jaya, Selangor, Malaysia
• ⁴ University Medical Center Hamburg-Eppendorf, Hamburg, Hamburg, Germany

Cellular mesenchymal-epithelial transition factor (c-MET), or hepatocyte growth factor receptor (HGFR), is a critical tyrosine kinase receptor in various solid tumors, including lung, breast, and liver cancers. This review examines the potential of integrating c-MET inhibition with immunotherapy to revolutionize cancer treatment. Moreover, the co-expression of c-MET and PD-L1 in tumors, such as hepatocellular carcinoma, underscores the prognostic significance and resistance to therapies. HGF from cancer-associated fibroblasts (CAFs) and mesenchymal stromal cells (MSCs) activates c-MET signaling in tumor cells and myeloid-derived suppressive cells (MDSCs), leading to metabolic reprogramming and secretion of Indoleamine 2,3-dioxygenase (IDO), glutaminase (GLS), and arginase 1 (ARG1). This depletes immune cells by limiting essential amino acids. Tumor-MDSC collaboration induces immune suppression, offering targets for intervention to enhance c-MET-targeted immunotherapy. Furthermore, cisplatin-induced chemoresistance, mediated by increased HGF levels and subsequent PD-L1 expression, can also counteract c-MET inhibitors, restoring anticancer immunity. This combined approach can significantly improve clinical outcomes by addressing immune evasion and enhancing anti-tumor immunity. On the other hand, the emerging field of c-MET-specific chimeric antigen receptor (CAR) cell therapies, including CAR-T and CAR-NK cells, which offers a precise approach to treating c-MET+ malignancies and antibody-based drugs targeting c-MET, including monoclonal antibodies, bispecific antibodies, and antibody-drug conjugates, as delivery systems and anti-c-MET agents for c-MET+ cancer cells, are also discussed in the present review. By exploring the impact of c-MET inhibition on the accumulation and transition of tumor-associated neutrophils, macrophages, regulatory T cells (Tregs), other T cells, and NK cells, the significant clinical implications of c-MET targeting in cancer therapy are highlighted. Combined with conventional treatments, immunotherapies show promise in managing cancer overexpressing c-MET. The review also investigates the crosstalk between c-MET and TGF-β pathways and the galectin family, contributing to immune evasion and cancer cell invasiveness. 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.