Biomimetic photosynthesis nanoreactors based thylakoid synergy with metformin for reversing tumor immunosuppressive microenvironment therapy

The hypoxia-induced immunosuppressive tumor microenvironment (TME) significantly limits the effectiveness of various solid tumor therapies. In this study, we developed a biomimetic photosynthetic nanoreactor system, termed Met-Tk-PLGA (MTP), by incorporating thylakoid membranes (Tk-M) with PLGA microspheres encapsulating metformin (Met). This system generates oxygen (O 2 ) in situ within the TME via photosynthesis while releasing Met to reduce cellular O 2 consumption, thereby alleviating tumor hypoxia. In vitro experiments confirmed that the Tk-M of MTP produces substantial O 2 via photosynthesis and, in combination with Met, significantly suppressed hypoxia-related signaling pathway protein expression. In vivo studies using an oral squamous cell carcinoma (OSCC) mouse model demonstrated that this combination therapy inhibited tumor growth and reversed hypoxia-induced immunosuppression in the TME, thereby enhancing antitumor immune responses. This dual strategy, alleviating tumor hypoxia through Tk-M−mediated O 2 generation and Met-induced reduction in O 2 consumption, offers a promising therapeutic approach to address tumor hypoxia.