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Abstract Organ-on-a-chip (OoC) systems are microfluidic technologies that replicate human physiology and disease conditionsex vivo, offering a promising alternative to animal models in preclinical drug testing and fundamental biological studies. Traditionally, OoCs systems are fabricated using conventional soft-lithography techniques with polydimethylsiloxane (PDMS) primarily due to its excellent inherent properties, including gas permeability, optical transparency, and biocompatibility. However, PDMS presents several notable shortcomings, most its limited scalability, which have prompted the search for more rapid and scalable fabrication processes. In this study, we present a cost-effective, efficient, and rapid design, development, and prototyping process for a microfluidic tumor-on-a-chip (TOC) platform technology for applications in cancer research and drug screening. Specifically, we present a novel 3D-printed, closed-system TOC device (i.e. Biochip) featuring distinct yet interconnected tumor and stromal regions, separated by an array of trapezoidal microposts, and fabricated with high precision and fidelity. The proposed Biochip was fabricated utilizing vat polymerization with a biocompatible resin and was compared alongside a conventional PDMS-glass (PDMS-G) and PDMS-laminate (PDMS-L) TOCs to evaluate its biological outcomes. The fabricated Biochip supported closed-channel 3D cell culture for testing up to 5 d. Using two triple-negative breast cancer cells, namely SUM-159 and MDA-MB-231, we further assessed and cross compared cellular migration, viability, and morphology across the Biochip, PDMS-G, and PDMS-L platforms. Overall, this work establishes a 3D-printed Biochip as a robust, cost-effective, and time-saving alternative to PDMS-based OoC, and specifically TOC systems. 

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. 

A human-relevant 3D glioblastoma perivascular niche-on-a-chip (GPoC) captures tumor–immune–vascular interactions, providing a physiologically relevant platform to investigate microglia-mediated tumor progression and evaluate therapeutic strategies. 

Abstract Evolving knowledge about the tumor–immune microenvironment (TIME) is driving innovation in designing novel therapies against hard‐to‐treat breast cancer. Targeting the immune components of TIME has emerged as a promising approach for cancer therapy. While recent immunotherapies aim at restoring antitumor immunity, counteracting tumor escape remains challenging. Hence there is a pressing need to better understand the complex tumor–immune crosstalk within TIME. Considering this imperative, this study aims at investigating the crosstalk between the two abundant immune cell populations within the breast TIME—macrophages and T cells, in driving tumor progression using an organotypic 3D in vitro tumor‐on‐a‐chip (TOC) model. The TOC features distinct yet interconnected organotypic tumor and stromal entities. This triculture platform mimics the complex TIME, embedding the two immune populations in a suitable 3D matrix. Analysis of invasion, morphometric measurements, and flow cytometry results underscores the substantial contribution of macrophages to tumor progression, while the presence of T cells is associated with a deceleration in the migratory behavior of both cancer cells and macrophages. Furthermore, cytokine analyses reveal significant upregulation of leptin and RANTES (regulated on activation, normal T Cell expressed and secreted) in triculture. Overall, this study highlights the complexity of TIME and the critical role of immune cells in cancer progression.