Engineered probiotics couple photothermal cuproptosis with biomechanical disruption and immune activation

Living bacterial therapeutics face limitations from poor surface functionalization and a hostile tumor microenvironment. Here, we engineer EPACS (EcN@PDA/Au-CuS) by coating E. coli Nissle 1917 with polydopamine, which acts as an adhesive interfacial platform to direct the uniform in situ growth of Au-CuS heterojunctions across the bacterial surface. EPACS combines tumor colonization, high photothermal conversion, and stimuli-responsive Cu²⁺ release for combined cuproptosis-mediated photothermal therapy. Mechanistically, EPACS induces oxidative stress and mitochondrial dysfunction, triggering both cuproptosis and apoptosis, while atomic force microscopy (AFM) reveals dynamic biomechanical changes-an initial RhoA/F-actin-dependent cellular stiffening that is subsequently reversed by laser irradiation into irreversible cytoskeletal disruption and enhanced cell killing. In vivo, EPACS achieves effective tumor accumulation and photothermal heating, resulting in substantial tumor suppression with favorable biosafety. When combined with laser irradiation, EPACS reduces collagen deposition and α-SMA expression, indicating stromal remodeling, and AFM confirms photothermal disruption of tumor matrix mechanics. This biomechanical remodeling is accompanied by immune modulation-decreased M2-like macrophages and regulatory T cells-suggesting enhanced antitumor immunity. Overall, EPACS integrates biochemical damage, cuproptosis/apoptosis, biomechanical regulation, and immunomodulation, offering a promising combined cancer therapy.