Nano‐Biohybrid‐Induced Inflammatory Cancer Cell Death Reprograms Anti‐Tumor Immunity to Suppress Tumor Progression and Metastasis

ABSTRACT Cancer remains notoriously difficult to cure, largely due to the tumor cells' proliferation and metastatic. Immunotherapy acts on multiple stages of the immune cycle, including antigen release, presentation, and effector cell killing. However, its efficacy is limited by the immunosuppressive tumor microenvironment, where TGF‐β1 impairs dendritic cell (DCs) function via prosaposin (pSAP) downregulation and promotes metastasis by inducing epithelial‐mesenchymal transition (EMT). To address these challenges, we developed a nano‐biohybrid system, Cu‐Gd(OH) x (MET)@PSB, composed of Cu 2 + ‐doped Gd(OH) x nanoparticles loaded with the TGF‐β1 inhibitor metformin (MET) and engineered photothermal bacteria (PSB). PSB facilitates enhanced tumor‑specific accumulation through anaerobic tropism and provides photothermal conversion under near‑infrared (NIR) irradiation. Within the tumor microenvironment, Cu‑Gd(OH) x (MET)@PSB triggers pyroptosis‐cuproptosis‐mediated inflammatory cell death through the collaboration of ion disruption, photothermal action, and energy depletion. Concurrently, MET‑mediated TGF‑β1 downregulation restores pSAP function in DCs, thereby improving antigen processing and presentation to activate effector T cells. Furthermore, reduced TGF‑β1 levels inhibit the EMT process, alleviating immunosuppression and attenuating tumor migration and invasion. The Cu‑Gd(OH) x (MET)@PSB platform simultaneously initiates an inflammatory cell death‑driven immune‑activating cascade and suppresses EMT‑mediated immune evasion. This dual strategy effectively overcomes key limitations of current immunotherapy and enhances anti‐tumor immunity, offering a compelling approach to reinforce cancer immunotherapy.