Tumor vascular disruption represents an attractive yet underexplored therapeutic strategy in cancer nanomedicine. We previously developed a lipid nanoparticle (LNP)-based vascular disrupting strategy combining cyclic RGD peptide-modified LNPs delivering siRNA against Fas ligand (cRGD-LNP/siFasL) to tumor endothelial cells with STING agonist-loaded LNPs (STING-LNPs), which cooperatively induce tumor vascular collapse through type I interferon-dependent mechanisms. However, the determinants of therapeutic responsiveness remain poorly defined. Here, we elucidated tumor microenvironmental factors governing heterogeneous therapeutic responses across syngeneic tumor models. While the combination therapy elicited robust vascular disruption and antitumor efficacy in CT26 and Renca tumors in BALB/c mice, its efficacy was markedly attenuated in B16-F10 and LLC tumors in C57BL/6 mice, independent of host genetic background. In refractory LLC tumors, the gene silencing efficiency in tumor endothelial cells was substantially lower (∼40% vs. ∼79% in responsive tumors), resulting in limited vascular disruption. Transcriptomic profiling suggested that the enhanced extracellular matrix remodeling and augmented innate immune activation within the tumor microenvironment may increase the susceptibility of tumor vasculature to the combination therapy. Flow cytometric analyses demonstrated significantly higher expression of IFNAR1, mediating type I interferon signaling, in responsive tumors. Collectively, this study suggests the tumor-intrinsic immune and stromal features that dictate responsiveness to LNP-mediated vascular disrupting therapy and provides a mechanistic framework for optimizing next-generation vascular-targeted nanomedicines.
