B7-H3 (CD276) in exosome biogenesis and the tumor microenvironment: a new therapeutic nexus

Tumor-derived exosomes are powerful mediators of cancer progression, influencing the tumor microenvironment (TME) to promote immune evasion, metastasis, and therapy resistance. B7-H3 (CD276), a member of the B7 immune checkpoint family, is gaining attention as a multifunctional promoter of tumor progression. In addition to its well-known expression on tumor and immune cells, B7-H3 is also enriched in exosomes, where it influences both extracellular vesicle production and signaling. This review examines how B7-H3 impacts exosome biology and contributes to tumor progression. We discuss the mechanisms of exosome biogenesis, including ESCRT-dependent and ESCRT-independent pathways. Emerging evidence indicates that B7-H3 enhances vesicular release, remodels cargo composition, and modulates recipient cell behavior. Mechanistically, B7-H3 activates pathways such as STAT3, PI3K, and lipid metabolism, thereby amplifying oncogenic signaling and promoting a pro-tumor TME. Clinically, B7-H3-enriched exosomes show promise as diagnostic, prognostic, and predictive biomarkers in colorectal, prostate, and non-small cell lung cancers. Additionally, we discuss strategies for therapeutically targeting exosomal B7-H3, including monoclonal and bispecific antibodies, CAR-T cells, and exosome inhibitors, as well as their potential synergy with immunotherapies. Overall, current evidence positions B7-H3 as a crucial link between checkpoint proteins and exosome-mediated cancer progression, offering new avenues for biomarker development and precision oncology.