Bacteria engineered with intracellular and extracellular nanomaterials for hierarchical modulation of antitumor immune responses.

Induction of immunogenic cell death (ICD) by hyperthermia can initiate adaptive immune responses, emerging as an attractive strategy for tumor immunotherapy. However, ICD can induce proinflammatory factor interferon-γ (IFN-γ) production, leading to indoleamine 2,3-dioxygenase 1 (IDO-1) activation and an immunosuppressive tumor microenvironment, which dramatically reduces the ICD-triggered immunotherapeutic efficacy. Herein, we developed a bacteria-nanomaterial hybrid system ( CuS VNP20009 NB ) to systematically modulate the tumor immune microenvironment and improve tumor immunotherapy. Attenuated Salmonella typhimurium (VNP20009) that can chemotactically migrate to the hypoxic area of the tumor and repolarize tumor-associated macrophages (TAMs) was employed to intracellularly biosynthesize copper sulfide nanomaterials (CuS NMs) and extracellularly hitchhike NLG919-embedded and glutathione (GSH)-responsive albumin nanoparticles (NB NPs), forming CuS VNP20009 NB . After intravenous injection into B16F1 tumor-bearing mice, CuS VNP20009 NB could accumulate in tumor tissues and repolarize TAMs from the immunosuppressive M2 to immunostimulatory M1 phenotype and release NLG919 from extracellular NB NPs to inhibit IDO-1 activity. Under further near infrared laser irradiation, intracellular CuS NMs of CuS VNP20009 NB could photothermally induce ICD including calreticulin (CRT) expression and high mobility group box 1 (HMGB-1) release, promoting intratumoral infiltration of cytotoxic T lymphocytes. Finally, CuS VNP20009 NB with excellent biocompatibility could systematically augment immune responses and significantly inhibit tumor growth, holding great promise for tumor therapy.