Abstract
Immunotherapy, particularly immune checkpoint blockade (ICB), has opened the era of modern oncology, offering significant promise for modern oncology. However, the efficacy of immunotherapy is frequently curtailed by the immunosuppressive tumor microenvironment (ITM), a milieu shaped by tumor metabolic reprogramming. Herein, a novel tumor microenvironment-responsive nanocapsules (DNMCs) were developed that simultaneously modulate tumor metabolism and the ITM to enhance the effectiveness of chemo-immunotherapy. DNMCs consist of an acidic and redox-sensitive metal-organic framework (MOF) encapsulating Doxorubicin (DOX) and the indoleamine-2,3-dioxygenase1 (IDO1) inhibitor NLG919. In the tumor microenvironment, DNMCs degrade, rapidly releasing DOX and NLG919. DOX induces immunogenic cell death (ICD), while NLG919 regulates amino acid metabolism by modulating IDO1 activity, thereby reversing the immunosuppressive of ITM. Consequently, DNMCs elicit effective anti-tumor immune responses, characterized by an increased density of tumor-infiltrating CD8(+) cytotoxic T cells as well as depletion of immunosuppressive regulatory T cells (Tregs), thus effectively suppressing pancreatic cancer growth in KPC mice through combined chemo-immunotherapy. Overall, DNMCs exhibit significant tumor growth inhibition in pancreatic cancer patient-derived organoids (PDOs) and mouse models. This study presents a promising approach to enhancing chemo-immunotherapy by targeting tumor metabolic reprogramming and augmenting immune response against malignant tumors.