The induced expansion of tumor-initiating cells (T-ICs) upon repeated exposure of
tumors to chemotherapeutic drugs forms a major cause for chemoresistance and
cancer metastasis. Here, a tumor-microenvironment-responsive
hydrogel patch is designed to modulate the plasticity of T-ICs in
triple-negative breast cancer (TNBC), which is insensitive to
hormone- and HER2-targeting. The on-site formation of the
hydrogel network patches
tumors in a chemoresistant TNBC murine model and senses intratumoral
reactive oxygen species for linker cleavage and payload release. Patch-mediated inhibition of the
histone demethylase lysine-specific demethylase 1 (LSD1) epigenetically regulates the switch of T-ICs from self-renewal to differentiation, rehabilitating their chemosensitivity. Moreover, the
hydrogel patch enhances
tumor immunogenicity and increases T-cell infiltration via epigenetic activation of innate immunity. A single-dose of the
hydrogel patch harboring LSD1 inhibitor and
chemotherapy agent efficiently suppresses
tumor growth, postsurgical relapse, and
metastasis. The superior efficacy against multidrug resistance further reveals the broad applicability of epigenetic remodeling
hydrogel patches.