Work

Identification of c‐Met on Tumor Cells as a Novel Receptor for B7‐H3 Entails Implications for Cancer Cell Stemness and Targeted Therapy

Year: 2025

Type: article

Abstract: The immune checkpoint molecule B7-H3 is upregulated in many solid tumors, and B7-H3-targeted immunotherapies are in clinical trials. Recently, a growing body of research has highlighted the presence of tumor cell intrinsic while immune cell-independent functions of B7-H3 in tumorigenesis and cancer cell stemness. However, its receptors and mechanisms of action on cancer cells remain poorly understood. Here, we report that c-Met, a canonical oncogenic receptor tyrosine kinase on cancer cells, is identified as a novel binding protein for B7-H3. The binding between c-Met and B7-H3 directly activates the c-Met/STAT3 signaling cascade, promoting cancer cell stemness in both colorectal cancer and glioblastoma-derived tumor cells. More importantly, we evaluated the translational implications of this discovery by screening a high-affinity antibody designed to selectively disrupt the interaction between B7-H3 and c-Met, demonstrating strong anti-tumor activities, surpassing that of the B7-H3-specific antibody lacking the blocking capability. Combination therapy of this newly developed interaction blocking antibody with c-Met inhibitor results in significantly improved therapeutic effects in inhibiting tumor growth. These findings shed light on previously undisclosed interaction of B7-H3 to c-Met on cancer cells, thereby indicating a new mechanism of cancer cell stemness and intervention pathway of molecular targeted therapy.

Source: MedComm

DOI: 10.1002/mco2.70332