A deformable Bacillus subtilis with gut homing for tumor treatment via bacterial metabolism-facilitated synergistic approach for starvation, chemotherapy, and immunotherapy.

Abstract

Cancer treatment remains a critical global health challenge, which often requires multimodal and targeted therapeutic strategies, yet integrating these modalities typically demands complex formulations. Oncolytic bacterial therapy offers unique opportunities for targeted drug delivery and immune modulation, yet clinical translation has been hindered by safety concerns and tedious engineering modification. Here, we report a deformable Bacillus subtilis (DBS), constructed through one-step cisplatin-induced morphological transformation that elongates the bacterium while simultaneously incorporating chemotherapeutic payloads. The resulting DBS integrated three synergistic antitumor mechanisms: Chemotherapy, Starvation, and Immunotherapy. Metabolically, DBS actively consumes glucose and lactate within the tumor microenvironment (TME), thereby depriving tumor cells of key nutrients and reshaping the microenvironment to become more permissive to therapy. Concurrently, anaerobe-targeting DBS releases the encapsulated cisplatin locally in the TME, enabling direct cytotoxic killing while limiting systemic exposure. Furthermore, DBS leverages its intrinsic immunogenicity to potentiate immune cell activation, while its elongated morphology prolongs tumor retention and facilitates enhanced interactions with infiltrating immune cells. Proteases secreted by DBS hydrolyze the extracellular matrix, facilitating immune cell infiltration and boosting anti-tumor immune responses. Surprisingly, DBS exhibits intestinal homing and is safely cleared through fecal excretion after treatment, minimizing systemic side effects. This study presents an efficient and safe live-bacterial platform for cancer therapy, underscoring the broad potential of bacterial morphology engineering as a facile strategy to integrate multiple synergistic antitumor mechanisms within a single microbial therapeutic.