Tumor vasculature-mediated formation of tertiary lymphoid structures: unraveling spatiotemporal coupling to optimize...

The tumor vascular system is critical within the tumor microenvironment (TME), not only supplying nutrients to tumor cells but also providing a structural framework and functional niche essential for the formation of tertiary lymphoid structures (TLSs). Studies have demonstrated that TLSs exhibit distinct perivascular localization in chronically inflamed tissues, suggesting a spatiotemporal coupling between angiogenesis and TLS formation. Vascular endothelial cells secrete pro-angiogenic factors and chemokines that regulate angiogenesis and can modulate TLS maturation and functionality by shaping lymphocyte recruitment and spatial distribution. Anti-angiogenic therapy can restore the abnormal structure and function of the tumor vascular system toward a more normal state, a process referred to as tumor vessel normalization. Although combining anti-angiogenic agents with immune checkpoint inhibitors (ICIs) has yielded synergistic therapeutic effects across various human solid tumors, this strategy still faces persistent challenges in precisely defining the therapeutic window and accurately identifying responsive patient populations. Consequently, tumor vessel normalization together with the dynamic evolution of TLSs collectively constitute a highly valuable "dual biomarker system," enabling real-time assessment of therapeutic responses and predictive insights to guide clinical treatment decisions. This review comprehensively examines the molecular mechanisms governing the regulation of TLS formation, highlighting key molecules and signaling pathways associated with vessel normalization. By critically integrating clinical trial data, the review delineates the potential benefits and existing bottlenecks of vasculo-immunological combination therapies and proposes novel strategies aimed at enhancing TLS functionality through precise spatiotemporal modulation of the vessel normalization window to overcome current therapeutic limitations of combined immunotherapy and anti-angiogenic strategies.