In Situ Biosynthesis of Pd Nanocrystals in Bifidobacterium Bioreactor as Dual Immune Stimulators for Immuno-Chemodynamic Therapy of Cold Tumor.

The intrinsic low immunogenicity of tumors remains a major limitation for cancer immunotherapy. Herein, a Bifidobacterium breve lw01-based bioreactor (lw01@Pd) was engineered to facilitate the intracellular in situ biosynthesis of palladium nanocrystals (Pd NCs) via carbon monoxide (CO) reduction to alleviate the immunosuppression of cold tumors. The intrinsic hypoxic targeting capability of lw01 in solid tumors enables the selective tumor colonization of lw01@Pd and synchronously minimizes off-target effects. Once within the tumor microenvironment (TME), the engineered lw01@Pd release Pd NCs via Xenophagy-mediated degradation within tumor cells, which then induce oxidative damage to both tumor cells and lw01 carrier. This oxidative stress not only induces the immunogenic cell death (ICD) of tumor cells, but also triggers the lysis of lw01, resulting in the release of damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). The concurrent presence of DAMPs and PAMPs promotes the maturation of dendritic cells (DCs) and facilitates antigen presentation, which in turn activates CD8+ T cells-mediated adaptive immune response. This probiotic nano-catalytic system demonstrates significant immunotherapeutic potential, offering new perspectives on overcoming the immune tolerance of cold tumors.