Microfabricated Organ-Specific Models of Tumor Microenvironments

Abstract

Despite the advances in detection, diagnosis, and treatments, cancer remains a lethal disease, claiming the lives of more than 600,000 people in the United States alone in 2024. To accelerate the development of new therapeutic strategies with improved responses, significant efforts have been made to develop microfabricated in vitro models of tumor microenvironments (TMEs) that address the limitations of animal-based cancer models. These models incorporate several advanced tissue engineering techniques to better reflect the organ- and patient-specific TMEs. Additionally, microfabricated models integrated with next-generation single-cell omics technologies provide unprecedented insights into patient's cellular and molecular heterogeneity and complexity. This review provides an overview of the recent understanding of cancer development and outlines the key TME elements that can be captured in microfabricated models to enhance their physiological relevance. We highlight the recent advances in microfabricated cancer models that reflect the unique characteristics of their organs of origin or sites of dissemination.

Keywords: MPS; TME; carcinogenesis; metastasis; microfabricated model; microphysiological systems; tumor microenvironment.

Figure 1

Elements of the TME and microfabricated breast TME models. (a) The TME is a complex landscape composed of multiple elements: cells, ECM, geometrical constraints, and physical stresses. Panel adapted from images created in BioRender; Oh, J. 2025. https://BioRender.com/m78b386. (b) Microfabricated model of breast tumor-stroma interactions. Panel adapted from Reference (CC BY 4.0) (c) Microfabricated model of breast tumor hypoxia. Panel adapted with permission from Reference ; copyright 2022 American Chemical Society. Abbreviations: BMSC, bone marrow stromal cell; ECM, extracellular matrix; FDR, false discovery rate; NES, normalized enrichment score; OXPHOS, oxidative phosphorylation; PC, polycarbonate; PDMS, polydimethylsiloxane; TME, tumor microenvironment.

Figure 2

Relevant organ structure and microfabricated lung- and liver-specific TME models. (a–d) Lung models. (a) Lung anatomy and physiology. Panel adapted from images created in BioRender; Oh, J. 2025. https://BioRender.com/b26f027. (b) Human vascularized solid lung tumor-on-a-chip for high-content drug screening. Tumor spheroids made from lung cancer cells (green) and endothelial cells (red) are cultured within a hydrogel containing endothelial cells and fibroblasts, which vascularize the tumor spheroids. Microbeads (blue) are introduced to the established vasculature to confirm its perfusability. Paclitaxel is delivered through the established vasculature, and its tumor-killing effect is demonstrated. Panel adapted with permission from Reference ; copyright 2019 American Chemical Society. (c) Schematic of the multiorgan microfluidic chip for modeling brain metastasis of lung cancer cells. Panel adapted from Reference (CC BY-NC-ND 4.0). (d) Concept and technical advantage of All-in-One-IMPACT platform for establishing vascularized tumor spheroid models. Panel adapted with permission from Reference ; copyright 2022 Wiley Periodicals LLC. (e–h) Liver models. (e) Liver anatomy and physiology. Panel adapted from images created in BioRender; Oh, J. 2025. https://BioRender.com/t49q016. (f) Biomimetic platform for recapitulating liver cancer (HCC-on-a-chip), and evaluation of NK-92 cell cytotoxicity against HCC cell HCCLM3 with or without human hepatic stellate cells. Panel adapted from Reference (CC BY-NC-ND 4.0). (g) Establishing HCC organoids from needle biopsies of HCC patients. Panel adapted from Reference (CC BY-NC-ND 4.0). (h) Schematic of dual oxygen gradient chip for elucidating oxygen gradient–induced intratumoral and interpatient heterogeneity in HCC. Panel adapted from Reference (CC BY 4.0). Abbreviations: BBB, blood–brain barrier; EC, endothelial cell; HCC, hepatocellular carcinoma; NK, natural killer; PDX, patient-derived xenograft; SC, stromal cell; TME, tumor microenvironment.

Figure 3

Relevant organ structure and microfabricated brain- and bone-specific TME models. (a–d) Brain models. (a) Brain anatomy and physiology. Panel adapted from images created in BioRender; Oh, J. 2025. https://BioRender.com/j84i307. (b) Microdevice for recapitulating the PVN within the GBM. The microdevice has three compartments: tumor, stroma, and vascular (fluorescence image). Panel adapted from Reference (CC BY 4.0). (c) Model of 3D human GBM integrated with triculture BBB (human brain endothelial cells, human astrocytes, and human brain vascular pericytes), and schematic of the engineered GBM-BBB model, where GBM-induced angiogenesis is observed. Panel adapted from Reference (CC BY 4.0). (d) 3D-bioprinted GBM model integrated with a noninvasive, fast, deep-tissue imaging system. The captured images are 3D reconstructed for longitudinal volumetric assessment before and after drug treatment. Panel adapted from Reference (CC BY-NC 4.0). (e–h) Bone models. (e) Hierarchical structure of bone tissue. Trabecular bone has a porous cavity structure. Compact bone is composed of dense collagen lamellae. Panel adapted from images created in BioRender; Lee, J. 2025. https://BioRender.com/w51f254. (f) Two-compartment scaffold mimics healthy bone and tumor tissue, which recapitulates the tumor progression near bone tissue. Panel adapted from Reference (CC BY 4.0). (g) 3D electrospun and (h) 3D-printed scaffolds reproduced bone tissue complexity; subsequently added human prostate tumor cells reproduced bone tumor progression. Panel g adapted from Reference ; copyright 2019 Elsevier Ltd. Panel h adapted from Reference (CC BY-NC 4.0). (i) Natural bone-based models: (i) Bovine decellularized trabecular bone demonstrating osteolysis by human osteosarcoma. Panel adapted from Reference ; copyright 2017 Mary Ann Liebert, Inc. (ii) Microfluidic chip including a 3D trabecular bone recapitulating bone tumor development. Panel adapted from Reference (CC BY 4.0). Abbreviations: 2GMFMT, second-generation mesoscopic fluorescence molecular tomography; BBB, blood–brain barrier; ECM, extracellular matrix; GBM, glioblastoma multiforme; hFOB, human fetal osteoblast; HUVEC, human umbilical vein endothelial cell; LSCM, laser scanning confocal microscopy; MFMT, mesoscopic fluorescence molecular tomography; OM, osteogenic medium; PLGA, poly(lactic-co-glycolic) acid; PVN, perivascular niche; TCP, tricalcium phosphate; TME, tumor microenvironment; WFFM, wide-field fluorescence microscopy.

Figure 4

Microfabricated bone and marrow TME models. (a) Schematic of tumor cell dissemination, dormancy, and relapse while interacting with local tissue cellular, extracellular, and molecular microenvironments. Panel adapted from images created in BioRender; Lee, J. 2025. https://BioRender.com/k17w541. (b–e) Bone marrow TME models. (b) Bone marrow vascular TME models to recapitulate early-stage metastasis: (i) A perfusable vascular chip reproduces the extravasation of CTCs while allowing time-course fluorescent monitoring. Panel adapted from Reference (CC BY 4.0). (ii) A perivascular niche model, with and without BMSCs, reproduced the dormancy of DTCs and the role of endothelial cells. Panel adapted from Reference ; copyright 2013 Macmillan Publishers Ltd. (c) Scaffold-based bone marrow stromal TME to study the role of adipocytes: Silk-based scaffolds supported the coculture of bone marrow adipocytes and MM cells, demonstrating a decrease in the size of fat droplets in contact with cancer cells. Panel adapted from Reference (CC BY 4.0). (d) Chip-based bone marrow TME models to recapitulate vascular and endosteal niche complexities: (i) A vascular marrow-on-a-chip model consisting of marrow and vascular channels replicated clinically relevant hematopoietic toxicities. Panel adapted from Reference ; copyright 2020 Springer Nature Limited. (ii) Compartmentalized endosteal and vascular niches connected via perfusable vascular networks recapitulated the vascularized bone marrow metastasis TME. Panel adapted from Reference ; copyright 2021 Elsevier Ltd. (iii) Microstructures in a chip created bone marrow–mimicking central sinusoid, medullary cavity, and endosteal regions, which supported the in vivo–relevant replication of leukemia cell growth and chemoresistance. Panel adapted from Reference (CC BY-NC 4.0). (e–g) Bone TME models. (e) Triculture model consisting of BMSC-derived osteoblasts, THP-1-derived osteoclasts, and breast cancer cells (MDA-231) recapitulated bone metastatic TME and demonstrated cancer cell–dependent osteolytic and osteoblastic lesions. Panel adapted from Reference ; copyright 2023 Elsevier Ltd. (f) A microfluidic perfusion chamber filled with microbeads and osteocytes simulated in vivo–like ECM complexity and mechanical milieu. Subsequently introduced osteoblasts and prostate cancer cells recapitulated the bone metastatic TME. Panel adapted from Reference (CC BY 4.0). (g) An osteoid-mimicking demineralized bone paper preserves the intrinsic collagen structure of the bone matrix while retaining durability and semitransparency. Recapitulation of a bone remodeling cycle via coculture of reporter murine osteoblasts and bone marrow monocytes on demineralized bone paper under biochemical stimulation is demonstrated, with longitudinal fluorescent monitoring. Panel adapted from Reference (CC BY-NC 4.0) and Reference (CC BY 4.0). Abbreviations: BMSC, bone marrow stromal cell; CTC, circulating tumor cell; DTC, disseminated tumor cell; ECM, extracellular matrix; GFP, green fluorescent protein; hBMAT, human bone marrow adipose tissue; MM, multiple myeloma; RFP, red fluorescent protein, TME, tumor microenvironment.