CX3CL1 (Fractalkine) is a multifunctional inflammatory chemokine with a single receptor CX3CR1. The biological effects elicited by CX3CL1 on surrounding cells vary depending on a number of factors including its structure, the expression pattern of CX3CR1, and the cell type. For instance, the transmembrane form of CX3CL1 primarily serves as an adhesion molecule, but when cleaved to a soluble form, CX3CL1 predominantly functions as a chemotactic cytokine (Fig. 1.1). However, the biological functions of CX3CL1 also extend to immune cell survival and retention. The pro-inflammatory nature of CX3CR1-expressing immune cells place the CX3CL1:CX3CR1 axis as a central player in multiple inflammatory disorders and position this chemokine pathway as a potential therapeutic target. However, the emerging role of this chemokine pathway in the maintenance of effector memory cytotoxic T cell populations implicates it as a key chemokine in anti-viral and anti-tumor immunity, and therefore an unsuitable therapeutic target in inflammation. The reported role of CX3CL1 as a key regulator of cytotoxic T cell-mediated immunity is supported by several studies that demonstrate CX3CL1 as an important TIL-recruiting chemokine and a positive prognostic factor in colorectal, breast, and lung cancer. Such reports are conflicting with an overwhelming number of studies demonstrating a pro-tumorigenic and pro-metastatic role of CX3CL1 across multiple blood and solid malignancies.

This chapter will review the unique structure, function, and biology of CX3CL1 and address the diversity of its biological effects in the immune system and the tumor microenvironment. Overall, this chapter highlights how we have just scratched the surface of CX3CL1’s capabilities and suggests that further in-depth and mechanistic studies incorporating all CX3CL1 interactions must be performed to fully appreciate its role in cancer and its potential as a therapeutic target.