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of nutrients and therapeutic agents , while simultaneously recapitulating both 3D tissue
architecture and pathophysiological conditions 66,67 .

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A notable example is the work by Ayuso et al. , who engineered a tumor-
lymphatic microfluidic model that faithfully mimics the 3D organization and functional

characteristics (including endothelial barrier properties and lymphangiogenic potential)

of in vivo lymphatic vessels. This innovative platform was employed to study breast

cancer-associated lymphatic dysfunction through analysis of altered gene expression

patterns in lymphatic endothelial cells. As next-generation experimental tools, these

tumor-on-chip systems provide physiologically relevant platforms that are transforming

cancer research paradigms.

The application of microfluidics has yielded significant insights into fundamental

cancer mechanisms, such as collective cancer cell migration/invasion processes
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(Figure 3A) and hypoxia- mediated HIF pathways , substantially advancing both
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diagnostic and therapeutic development. Ao et al. demonstrated the clinical potential
of this technology by developing a "mini tumor chip" through tumor cell injection into

microwell arrays, enabling prediction of immunotherapy responses in just 24 hours - a

dramatic reduction compared to conventional in vitro culture durations. Similarly,

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Ruzycka et al. employed microfluidic platforms to model TMEs for metastatic lung
cancer investigation, establishing that these systems provide more physiologically

accurate assessment of nanomaterial toxicity and therapeutic efficacy while

simultaneously reducing reliance on animal models (Figure 3B).

The integration of 3D printing with microfluidic technology has significantly

accelerated the development of tumor-on-chip systems with enhanced physiological
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relevance. Behroodi et al. demonstrated this synergy by combining projected micro-
stereolithography (PµSL) 3D printing with CNC micromachining to fabricate large-

scale microfluidic molds, streamlining the production of high-resolution devices

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(Figure 3C). Meanwhile, Steinberg et al. engineered fully 3D-printed microfluidic
platforms capable of maintaining patient-derived multicellular spheroids for prolonged

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