The role of CXCL5 in tumor microenvironment: Regulatory mechanisms and therapeutic potential

C-X-C motif chemokine ligand 5 (CXCL5), also known as epithelial neutrophil-activating peptide 78 (ENA-78), is a pivotal member of the ELR⁺ CXC chemokine family, characterized by a conserved glutamic acid-leucine-arginine motif. CXCL5 plays a central regulatory role in shaping the tumor immune microenvironment (TIME). Its expression is regulated by transcription factors (NF-κB, STAT3, SP1, p53), epigenetic modifications (DNA methylation, histone acetylation, microRNAs), and cytokines/growth factors (IL-1β, TNF, EGF). These regulatory mechanisms shape CXCL5 function in inflammation and cancer. CXCL5 interacts with diverse immune cells, including tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), T lymphocytes, and myeloid-derived suppressor cells (MDSCs). These interactions establish an immunosuppressive microenvironment that drives tumor immune evasion, metastasis, and therapeutic resistance. Mechanistically, CXCL5 regulates the malignant phenotypes of tumor cells by activating signaling pathways including PI3K/AKT, JAK-STAT/NF-κB, and ERK/MSK1/Elk-1/snail. Recent preclinical studies highlight that blocking the CXCL5-CXCR2 axis reverses immunosuppression and improves immune checkpoint inhibitor efficacy. This review systematically maps the multidimensional regulatory network of CXCL5 in the TIME and summarizes its molecular interactions with immune cells. The therapeutic potential of targeting these pathways is also explored to inform novel immunotherapeutic combination strategies.