Triple-negative breast cancers (TNBCs) are associated with poor survival mediated by treatment resistance. TNBCs are fibrotic, yet little is known regarding how the extracellular matrix (ECM) evolves following therapy and whether it impacts treatment response. Analysis revealed that while primary untreated TNBCs are surrounded by a rigid stromal microenvironment, chemotherapy-resistant residual tumors inhabit a softer niche. TNBC organoid cultures and xenograft studies showed that organoids interacting with soft ECM exhibit striking resistance to chemotherapy, ionizing radiation, and death receptor ligand TRAIL. A stiff ECM enhanced proapoptotic JNK activity to sensitize cells to treatment, whereas a soft ECM promoted treatment resistance by elevating NF-κB activity and compromising JNK activity. Treatment-resistant residual TNBCs residing within soft stroma had elevated activated NF-κB levels, and disengaging NF-κB activity sensitized tumors in a soft matrix to therapy. Thus, the biophysical properties of the ECM modify treatment response, and agents that modulate stiffness-dependent NF-κB or JNK activity could enhance therapeutic efficacy in patients with TNBC.

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