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Abstract The prognosis of glioblastoma multiforme (GBM) remains dismal, despite standard treatment regimens. A key challenge in treating GBM is the persistence of glioma stem cells (GSCs) within the perivascular niche (PVN) – a protective tumor microenvironment (TME) that is often associated with inadequate drug penetration. Current preclinical models do not capture complexity of the human TME, particularly the vasculature and niche‐specific interactions that drive GBM progression. To overcome these limitations, an innovative 3Dex‐vivotumor‐on‐a‐chip (TOC) platform is engineered to accurately replicate the structural and functional characteristics of the PVN. Using this platform, this study demonstrates that monocyte membrane‐coated nanoparticles (MoNP) effectively target the abnormal tumor microvasculature, offering a promising approach to enhance drug delivery to these hard‐to‐reach GSCs. The results show that the therapeutic agent verteporfin, when delivered via MoNP, significantly inhibited GSC growth and invasiveness, while the free‐form drug showed minimal efficacy. Comprehensive transcriptomic profiling and cytokine analysis validated the TOC model's ability to reflect authentic GSC responses and confirmed that MoNP‐mediated verteporfin delivery effectively modulates key tumor‐related signaling pathways. This integrated TOC‐MoNP platform represents a clinically relevant tool that bridges the gap between traditional preclinical models and human disease, providing new opportunities for developing more effective GBM therapies. 

Abstract Solid tumors develop within a complex environment called the tumor microenvironment (TME), which is sculpted by the presence of other cells, such as cancer‐associated fibroblasts (CAFs) and immune cells like macrophages (Mφs). Despite the presence of immune cells, tumor cells orchestrate a tumor‐supportive environment through intricate interaction with the components of the TME. However, the specific mechanism by which this intercellular dialogue is regulated is not fully understood. To that end, the development of an organotypic 3D breast TME‐on‐a‐chip (TMEC) model, integrated with single‐cell RNA sequencing analysis, is reported to mechanistically evaluate the progression of triple‐negative breast cancer (TNBC) cells in the presence of patient‐derived CAFs and Mφs. Extensive functional assays, including invasion and morphometric characterization, reveal the synergistic influence of CAFs and Mφs on tumor cells. Furthermore, gene expression and pathway enrichment analyses identify the involvement of theKYNUgene, suggesting a potential immune evasion mechanism through the kynurenine pathway. Lastly, the pharmacological targeting of the identified pathway is investigated.