ECM characterization and 3D bioprinted models of NSCLC for investigating stiffness-dependent tumor behavior and drug response.

The heterogeneity and complex extracellular matrix (ECM) characteristics of non-small cell lung cancer (NSCLC) present significant challenges for understanding its pathological mechanisms and advancing precise treatment strategies. This study characterized the physicochemical properties of native NSCLC ECM to inform the biomimetic design of 3D models utilizing biomaterials and light-based 3D bioprinting technologies. A tunable 3D model was constructed that replicates the interfacial structures and matrix stiffness of both lung cancer tissue and adjacent normal tissue. This model elucidates the impact of matrix stiffness on cellular behaviors, including proliferation, invasion, and drug sensitivity, and delineates the role of the CCN1 gene under different mechanical conditions. Specifically, it demonstrates that a reduction in CCN1 expression within soft matrices can attenuate the migratory and proliferative capabilities of tumor cells. Furthermore, primary NSCLC patient-derived bioprinted tissues validated the model fidelity to clinical samples and its predictive potential for responses to combined chemotherapy and immunotherapy. This study establishes a versatile platform for NSCLC modeling and research, advancing biomaterial and bioprinting strategies to replicate the tumor microenvironment and optimize therapeutic approaches.