Hypoxia-activated PROTAC for dual inhibition of FAK and EGFR enables synergistic mechano-chemical cancer therapy.

Mechanical abnormalities in the tumor microenvironment (TME), such as matrix stiffening and hypoxia, drive tumor invasion and therapy resistance. Yet targeting these cues with spatial precision remains challenging. Here we present a hypoxia-responsive dual-warhead PROTAC (hrFP-E) that couples focal adhesion kinase (FAK) degradation with inhibition of epidermal growth factor receptor (EGFR), introducing a mechano-chemical therapy paradigm. hrFP-E is equipped with a nitroreductase (NTR)-sensitive motif activated in hypoxic regions to release a FAK degrader (FP) and an EGFR inhibitor (Erlotinib). In lung cancer models, hrFP-E induces near-complete FAK depletion (∼96-99%) and substantial EGFR pathway suppression (∼88%), resulting in synergistic anti-migration and anti-proliferation effects in both 2D and 3D assays. Mechanistically, FAK degradation stabilizes large focal-adhesions, alters actomyosin contractility, elevates ROS, and reduces collagen deposition, collectively reprogramming the TME. In vivo, hrFP-E achieves ∼66% tumor growth inhibition without overt toxicity while reducing tissue stiffness and collagen density. This platform is inherently modular and compatible with alternative oncogenic drivers and disease-specific gates. Our work establishes mechano-chemical therapeutics, spatiotemporally controlled degraders that rewire tumor mechanics alongside growth signaling, as a generalizable strategy for solid tumor treatment.