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

ABSTRACT: Aberrant tumor metabolic activities not only promotes the aggressiveness and proliferation of tumor cells in the harsh microenvironment in vivo, but also contributes to immune cell dysfunction and immunosuppressive TME. This phenomenon poses a major challenges 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 at 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 at Ce6/Lon for tumor metabolic regulation. Firstly, CM-ZIF8 at 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 at 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

ORGANISM(S): Mus musculus

PROVIDER: GSE237010 | GEO | 2025/07/31

REPOSITORIES: GEO

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Project description:Immunotherapeutics represent highly promising agents with the potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME) present in PDACs, which creates a barrier to effective immune surveillance. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiltration and the high numbers of tumor-associated immunosuppressive cells. We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition (VS-4718) dramatically limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells and immunosuppressive macrophages. We postulated that these desirable effects of FAK inhibition on the TME might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that VS-4718 rendered the previously unresponsive KPC mouse model responsive to anti-PD1 and anti-CTLA4 antagonists leading to a nearly tripling of survival times. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME thus rendering tumors more responsive to immunotherapy. We treated KP orthotopic tumor-bearing mice with vehicle and FAK inhibitor (FAKi) for 14 days, then extracted total RNA from tumor tissues.

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

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