Engineered Matrices Reveal Sulfation-Mediated Stress Adaptation and Drug-Specific Modulation of Chemotherapeutic Response

Engineering biomimetic extracellular matrices that isolate specific biochemical cues is essential for understanding how matrix chemistry regulates tumor cell behavior and therapeutic response. Aberrant sulfation due to proteoglycan expression is a hallmark of lung tumor matrices, yet its functional impact is difficult to study using conventional materials where mechanical and biochemical variables are coupled. To address this, mechanically matched sulfated alginate hydrogels are engineered to mimic the elevated sulfated glycosaminoglycan (sGAG) content of malignant ECM, enabling sulfation to be examined as a single, tunable variable. Within this system, ECM sulfation is shown to enhance tumor cell proliferation, promote oxidative and mitochondrial stress tolerance, suppress apoptotic signaling and attenuate the efficacy of cisplatin, gemcitabine and paclitaxel. Sulfated matrices preserve mitochondrial membrane potential, limit ROS accumulation, shift apoptotic gene expression toward a survival-favoring profile, selectively upregulate ABCB1-mediated efflux and modulate drug response through the PI3K/Akt-ABCB1 signaling axis. Functional inhibition of PI3K and ABCB1 uncovers drug-specific dependencies while dual pathway targeting completely restores chemotherapeutic sensitivity. These findings identify ECM sulfation as a potent regulator of stress adaptation and therapeutic efficacy in lung adenocarcinoma and underscore the importance of biomimetic ECM design in controlling tumor cell fate and drug response.