Background: X-C Motif Chemokine Ligand 2 (XCL2) is a 114 amino acid, structurally conserved chemokine involved in activating cytotoxic T cells. However, the pathophysiological mechanisms of XCL2 protein in various disease conditions, particularly cancer, remain poorly understood.

Methods: Bioinformatics was used to detect the expression of XCL2, the relationship between survival time and XCL2 in BLCA patients, the mutational status of XCL2, the role of XCL2 in the tumor immune microenvironment, and the sensitivity of XCL2-targeted drugs in 33 cancers. In vitro experiments were conducted to investigate the chemotactic effects of XCL2 expression on M1-type macrophages in human specimens and in isolated cancer cells.

Results: XCL2 expression was downregulated in tumor tissues and closely associated with the prognosis of human cancers. Furthermore, XCL2 affects DNA methylation, tumor mutation burden (TMB), microsatellite instability (MSI), and mismatch repair (MMR) in human cancers. The expression level of XCL2 significantly correlated with infiltrated immune cells, immunological pathways, and other immune markers. More importantly, we found that XCL2 was positively associated with T lymphocytes and macrophages in the transcriptome and single-cell sequencing data. Using multiple immunofluorescence staining, we found that the expression level of XCL2 was upregulated in many cells in pan-cancer samples, and the number of M1 macrophage marker CD68 and INOS-positive cells increased. 786O, U251, and MDA-MB-231 cells could recruit more M1 macrophages in vitro after overexpressing XCL2.

Conclusions: Our results reveal that XCL2 could act as a vital chemokine in pan-cancer and provide new targets and concepts for cancer treatment.