Harnessing microbial hydrogen for remodeling tumor microenvironment to potentiate collaborative chemo-immunotherapy

Chemo-immunotherapy is fundamentally limited by insufficient tumor specificity and immunosuppressive tumor microenvironment (TME). Here, an engineered probiotic CB@PPH is elaborately constructed to remodel tumor microenvironment for potentiating collaborative chemo-immunotherapy. Specifically, phenylboronic acid-modified hyaluronic acid-coated paclitaxel (PTX)-loaded PCN-224 (PPH) nanoparticles are covalently conjugated with Clostridium butyricum (CB) to develop CB@PPH. Due to tumor hypoxia-tropism, CB@PPH facilitates the precise intratumoral delivery of PPH, and in situ kills tumor cells by inhibiting the depolymerization of tubulin. Moreover, the enriched CB@PPH at tumor tissues could persistently produce abundant microbial H 2 . On the one hand, the generated intratumoral H 2 would induce severe mitochondrial destruction and disrupt redox homeostasis within tumor cells, collaboratively amplifying immunogenic cell death signaling. On the other hand, microbial H 2 acts as an immune modulatory agent, remodeling the immunosuppressive TME into a pro-immunogenic milieu that activate robust antitumor immune responses. In combination with αPD-1 therapy, the engineered CB@PPH significantly inhibits the growth of subcutaneous tumors, as well as effectively suppresses the progression of distant tumors with a tumor inhibition rate of 91.0 %. This work underscores the innovative potential of microbial H 2 -assited chemo-immunotherapy, presenting a paradigm for the development of cancer therapeutic strategies.