Biomimetic multifunctional nanodrugs enable regulating abnormal tumor metabolism and amplifying PDT-induced immunotherapy for synergistically enhanced tumor ablation

Aberrant tumor metabolic activities not only promote the aggressiveness and proliferation of tumor cells in the harsh microenvironment in vivo, but also contribute to immune cell dysfunction and immunosuppressive TME. This phenomenon poses a major challenge to cancer immunotherapy. Thus, tumor metabolic interventions might be a promising strategy to reverse immune suppression for boosting anti-tumor immunotherapy. Herein, biomimetic multifunctional nanodrugs (CM-ZIF8@Ce6/Lon) were constructed for collaborative tumor metabolic regulation and photodynamic (PDT) amplified immunotherapy. These nanodrugs were prepared by homotypic tumor cell membrane (CM)-camouflaged zeolitic imidazolate framework-8 (ZIF-8) nanoparticles embedded with photosensitizer (Chlorin e6, Ce6) and metabolic modulator (Lonidamine, Lon). We carried out a series of experiments to explore the possible mechanism of CM-ZIF8@Ce6/Lon for tumor metabolic regulation. Firstly, CM-ZIF8@Ce6/Lon could actively metastasis towards tumor cells based on the homotypic targeting property. Subsequently, the nanodrugs blocked tumor metabolic pathways and reduced metabolites accumulation, therefore reversing the immunosuppressive TME through releasing Lon. Meanwhile, the released Ce6 from these nanodrugs triggered PDT efficiency on the tumor suppression, and induced ICD effect to activate the cascade immune response. The regulation of tumor metabolism disorders synergistically augmented PDT-mediated immunotherapy through reduction of regulatory T cells, enhancement of CD8+ T cell infiltration and upregulation of inflammatory factors. As a result, CM-ZIF8@Ce6/Lon efficiently inhibited the primary and metastatic tumor. Overall, our study explored mechanism of tumor metabolic regulation to reverse the immunosuppressive TME and demonstrated the important potential of the synergistic anti-tumor. This multifunctional nanodrug may provide new insight for developing a promising therapeutic tool to reverse immunosuppression and boost anti-tumor immunotherapy.