Spatially compartmentalized fibrotic tumor microtissues via embedded coaxial 3D bioprinting for enhanced barrier function and drug resistance.

Fibrosis is a prominent feature of the tumor microenvironment (TME) that contributes to tumor progression and therapeutic resistance. Here, we developed an embedded coaxial 3D bioprinting strategy to fabricate spatially compartmentalized fibrotic tumor microtissues with controlled tumor-stromal organization. Compared with mixed spheroids, coaxial spheroids exhibited enhanced hypoxia, fibroblast activation, and ECM deposition, together with reduced drug penetration and increased therapeutic resistance. These responses were supported by molecular and functional analyses. Collectively, our findings show that controlled tumor-stromal organization is closely associated with fibrosis- and hypoxia-related drug resistance. The embedded coaxial bioprinting approach provides a reproducible and tunable engineering framework for systematically investigating how controlled variations in tumor-core diameter, stromal-shell thickness, and cellular positioning influence fibrotic tumor phenotypes and therapeutic responses in vitro.