Supramolecular net-suppressor drives tumor vascular-immune microenvironment remodeling with spatiotemporal synchronization for renal cancer therapy

Abstract

Advanced or metastatic renal cell carcinoma (RCC) responds poorly to current combination therapies, as anti-angiogenic agents and immune checkpoint inhibitors fail to act in a spatiotemporally synchronized manner. Consequently, their synergistic potential cannot be fully realized within the transient vascular normalization window. To address this, we developed microenvironment-Reprogramming and Integrated NetGuard (RING), an integrative multi-target peptide inhibitor. RING1 incorporates VEGF/Tie2-targeting and TIGIT-blocking modules within one molecule, enabling the simultaneous induction of vascular normalization, effector T cell infiltration, and immune checkpoint blockade. Its cyclic structure and incorporation of D-amino acids confer enhanced in vivo stability and promote tumor-specific accumulation. Upon enrichment, RING1 self-assembles into extensive nanonetworks, thereby amplifying target engagement and prolonging intratumoral retention. Compared to clinical combination therapy, RING1 enhanced vascular normalization by 1.8-fold, which subsequently reduced the population of immunosuppressive Tie2-expressing monocytes (TEMs) and elevated the secretion of IFN-γ and granzyme B. Notably, RING1 demonstrated superior tumor-suppressive and anti-metastatic efficacy, as well as improved biosafety, even in orthotopic metastatic models. Overall, RING1 represents a novel therapeutic strategy that remodels the tumor vascular-immune microenvironment with spatiotemporal synchronization via self-assembly, offering a promising alternative to conventional combination therapies.