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.