Chemically Engineered L. reuteri Delivering αPD‐L1 and Gallium Ions via Metal‐Phenolic Networks Potentiate Anti‐Tumor Immunity and Ferroptosis

ABSTRACT Bacterial‐based materials, leveraging their inherent hypoxia and immunosuppressive microenvironment‐targeting capabilities, immunomodulatory effects, and drug delivery advantages, have emerged as promising strategies to modulate the tumor microenvironment (TME) for converting immunologically “cold” tumors into “hot” ones. This study innovatively functionalizes Lactobacillus reuteri ( L. reuteri ) using metal‐phenolic networks (MPNs) to co‐deliver αPD‐L1 antibodies and gallium ions (Ga 3 + ) for synergistic anti‐tumor therapy. The MPN coating materials enable pH‐responsive drug release, whereby αPD‐L1 reverses immunosuppression and Ga 3 + disrupts tumor iron metabolism, mimicking Fe 3 + to induce selective ferroptosis. In vivo evaluations in B16 and LLC tumor‐bearing mouse models revealed that functionalized L. reuteri had the potential to reprogram the tumor immune microenvironment and significantly enhanced tumor regression. This system achieved multifunctional tumor regression in vivo, integrating bacterial hypoxia‐driven chemotaxis, MPN‐mediated ferroptosis, and immune checkpoint inhibitors (ICIs)‐driven immune activation. Thus, the multifunctional materials offer a novel strategy for treating refractory or immunologically “cold” tumors.