Tehran University of Medical Sciences Iranian Journal of Allergy, Asthma and Immunology 1735-1502 24 5 2025 09 16 581 586 Xiangrong Luo The Central Hospital of Shaoyang, Shaoyang, China AND Department of Colorectal & Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China Bin Dai The Central Hospital of Shaoyang, Shaoyang, China Zengzhe Xie The Central Hospital of Shaoyang, Shaoyang, China Sen Zhang Department of Colorectal & Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China 2025 03 10 2025 04 28 Colorectal cancer (CRC) remains a significant global health challenge, characterized by high morbidity and mortality. Despite advances in surgical techniques, chemotherapy, targeted therapies, and immunotherapy, many CRC cases exhibit treatment resistance and immune evasion, necessitating the identification of novel therapeutic targets. Follistatin-like protein 3 (FSTL3) has recently emerged as a key regulator in CRC progression, influencing immune suppression and therapy resistance. FSTL3 modulates the tumor microenvironment by promoting epithelial-mesenchymal transition (EMT), sustaining β-catenin signaling, and stabilizing c-Myc, which collectively enhance tumor invasiveness and metastatic potential. Additionally, FSTL3 contributes to immune evasion by upregulating immune checkpoint molecules such as programmed death-ligand 1  (PD-L1) and indoleamine-2,3-dioxygenase 1 (IDO1), thereby suppressing cytotoxic T-cell activity. High FSTL3 expression correlates with poor prognosis and resistance to conventional chemotherapy, targeted agents, and immune checkpoint inhibitors. Given its pivotal role in CRC pathophysiology, FSTL3 represents a promising biomarker for disease prognosis and a potential therapeutic target. Future research should focus on developing FSTL3-targeted interventions, including monoclonal antibodies, small-molecule inhibitors, and combination strategies with immunotherapy. Understanding the precise molecular mechanisms underlying FSTL3-mediated tumor progression and immune escape will be essential for translating these insights into clinical applications. https://ijaai.tums.ac.ir/index.php/ijaai/article/view/4381 https://ijaai.tums.ac.ir/index.php/ijaai/article/download/4381/2202