Photodynamic therapy (PDT) capable of eliciting a robust antitumor immune response has been considered an attractive therapeutic approach. However, adaptive immune resistance in PDT underlines the need to develop alternative strategies. The exquisite power of checkpoint blockade can be harnessed to reinvigorate antitumor immune response. Here, we demonstrate that PDT-triggered adaptive immune resistance can be overcome by inactivating indoleamine 2,3-dioxygenase 1 (IDO-1). We rationally designed a tumor-microenvironment-sheddable prodrug vesicle by integrating a PEGylated photosensitizer (PS) and a reduction-sensitive prodrug of IDO-1 inhibitor. The prodrug vesicles were inert during the blood circulation, whereas they specifically accumulated and penetrated at the tumor site through matrix metalloproteinase-2 (MMP-2)-mediated cleavage of the PEG corona to achieve fluorescence-imaging-guided photodynamic therapy (PDT). Compared to PDT alone, the prodrug-vesicle-mediated combination immunotherapy provoked augmented antitumor immunity to eradicate the tumor in both CT26 colorectal and 4T1 breast immunocompetent mouse models. The prodrug vesicles dramatically suppressed tumor reoccurrence, particularly in overexpressing IDO-1 tumor models, i.e., CT26. This study might provide novel insight into the development of new nanomedicine to enhance the efficacy of photodynamic immunotherapy while addressing the adaptive immune resistance.
Multidrug resistance (MDR) is an issue that is not only related to cancer cells but also associated with the tumor microenvironments. MDR involves the complicated cancer cellular events and the crosstalk between cancer cells and their surroundings. Ideally, an effective system against MDR cancer should take dual action on both cancer cells and tumor microenvironments. The authors find that both the drug‐resistant colon cancer cells and the protumor M2 macrophages highly express two nutrient transporters, i.e., secreted protein acidic and rich in cysteine (SPARC) and mannose receptors (MR). By targeting SPARC and MR, a system can act on both cancer cells and M2 macrophages. Herein the authors develop a mannosylated albumin nanoparticles with coencapsulation of different drugs, i.e., disulfiram/copper complex (DSF/Cu) and regorafenib (Rego). The results show that combination therapy of DSF/Cu and Rego efficiently inhibits the growth of drug‐resistant colon tumor, and the combination has not been reported yet for use in anticancer treatment. The system significantly improves the treatment outcomes in the animal model bearing drug‐resistant tumors. The therapeutic mechanisms involve enhanced apoptosis, upregulation of intracellular ROS, anti‐angiogenesis, and tumor‐associated macrophage “re‐education.” This strategy is characterized by dual targeting to and the simultaneous action on cancer cells and M2 macrophages, with biomimetic codelivery of a novel drug combination.
Gefitinib is a first-line therapy in the EGFR-mutated nonsmall cell lung cancer (NSCLC). However, the development of drug resistance is almost unavoidable, thus leading to an unsustainable regimen. EGFR mutation is the major cause responsible for the molecular-targeting therapy failure in NSCLC. Although the recently approved osimertinib is effective for the EGFR-positive NSCLC, the osimertinib-resistant EGFR mutation is rapidly developed, too. In this study, we proposed a tumor-associated macrophage (TAM) reprogramming strategy for overcoming the EGFR-associated drug resistance via a dual-targeting codelivery system of gefitinib/vorinostat that acted on both TAM with overexpression of mannose receptors and the HER-2 positive NSCLC cells. The trastuzumab-modified, mannosylated liposomal system was able to repolarize the protumor M2 phenotype to the antitumor M1 and cause the elevating ROS in the cancer cells, consequently modulating the intracellular redox balance via ROS/NOX3/MsrA axis. The suppressed MsrA facilitated the EGFR degradation through 790M oxidation by ROS, thus resensitizing the EGFR-positive cells to gefitinib. The dual-targeting codelivery and TAM-reprogramming strategies provided a potential method for rescuing the EGFR-caused resistance to tyrosine kinase inhibitor treatment.
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