Spatiotemporal dynamic regulation of the CX3CL1-CX3CR1 axis: A double-edged sword in the tumor immune microenvironment and new strategies for precision therapy.

The CX3CL1-CX3CR1 signaling axis is a key yet functionally contradictory regulatory hub within the tumor immune microenvironment (TME), with its output shaped by spatiotemporal dynamics. This review seeks to address the core scientific question of how this axis mediates both pro-tumor and anti-tumor effects simultaneously by analyzing a multi-layered regulatory framework. The duality of its function is rooted in two main mechanisms: (1) the regulation of CX3CL1 ligand cleavage by ADAM10/17 proteases, which determines the balance between membrane-bound (mCX3CL1, mediating adhesion) and soluble (sCX3CL1, mediating chemotaxis) isoforms; (2) the expression gradient of its sole receptor CX3CR1 on immune cells, which functions as a molecular code that precisely programs cell differentiation trajectories, such as the differentiation of CD8T cells from a stem-like state to a terminally exhausted state. Specific TME signals (such as TGF-β in pancreatic ductal adenocarcinoma (PDAC) and TLR4 signaling in colorectal cancer (CRC)) integrate these mechanisms and ultimately dictate distinct functional outputs. We propose that interventions targeting this axis must move beyond traditional agonist/antagonist approaches toward spatiotemporally specific precision control strategies, including intelligent delivery systems, CRISPR-based cell engineering, and AI-driven personalized treatments. Rationally reprogramming the functional orientation of this axis holds promise in overcoming immune checkpoint inhibitor resistance and provides a theoretical foundation for the development of a new generation of cancer immunotherapies.