S100A8/A9 as a key player in colorectal cancer: from diagnosis to therapeutic targeting

Abstract

S100A8/A9, a key member of the calcium-binding protein family, exerts multiple biological effects through its aberrant expression, and serves as an important regulatory factor in the development and progression of colorectal cancer (CRC). Its activity remodels the tumor microenvironment (TME) by amplifying inflammatory responses, establishing immunotolerant conditions, promoting metastatic tumor phenotypes, and forming pre-metastatic and angiogenic niches. These processes suppress anti-tumor immunity, enhance tumor invasion and metastasis, and are associated with poorer prognosis, particularly in advanced-stage CRC. Despite the complexity of its regulatory network, S100A8/A9 represents a valuable potential therapeutic target. This review systematically summarizes the biological properties, clinical significance, and tumor microenvironment-related mechanisms of S100A8/A9 in CRC, with emphasis on inflammation, immune regulation, invasion, metastasis, biomarker potential, and therapeutic targeting. We further discuss emerging S100A8/A9-based intervention strategies, including direct molecular targeting, receptor-pathway blockade, natural-product modulation, combination therapy, and precision-delivery approaches, aiming to clarify both the translational opportunities and limitations of S100A8/A9-directed precision management in CRC.