CXC Chemokine-Driven Vascular Reprogramming: Modulating Tumor Vasculature to Boost Therapeutic Response

Aberrant tumor vasculature drives hypoxia, immune exclusion, and therapeutic resistance. However, current vascular normalization strategies remain primarily VEGF-centered, relying on morphological and perfusion metrics with limited molecular readouts to monitor vessel function. This highlights the need for alternative frameworks to identify therapeutic windows and enhance vascular-immune strategies. Here, we introduce a chemokine-centered perspective that positions the CXC chemokine network as a dynamic regulator of vascular functionality. We highlight three core mechanistic dimensions: bidirectionality, temporal dynamics, and tissue specificity, and further emphasize the functional synergy emerging from their network-level interactions. Building on these features, we propose the functional vascular normalization score (FVNS) and the chemokine-guided vascular normalization window (VNW) as molecular tools for real-time vascular assessment and therapeutic stratification. Finally, we outline CXC-targeted strategies, including CXCR2/CXCR4 blockade, CXCL9/10/11 augmentation, and spatiotemporally controlled delivery platforms, which may extend and personalize the VNW. This chemokine-focused paradigm provides a functional and implementable approach for the integration of vascular normalization and immune modulation in cancer therapy.