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Nanoscale reduced graphene oxide-mediated photothermal therapy together with IDO inhibition and PD-L1 blockade synergistically promote antitumor immunity
摘要： Despite the potential efficacy of immune checkpoint blockade for effective treatment of cancer, this therapeutic modality is not generally curative and only a fraction of patients respond. Combination approaches provide strategies to target multiple antitumor immune pathways to induce synergistic antitumor immunity. Here, a multi-combination immunotherapy including photothermal therapy (PTT), indoleamine-2,3-dioxygenase (IDO) inhibition and programmed cell death-ligand 1 (PD-L1) blockade is introduced for inducing synergistic antitumor immunity. We designed a multifunctional IDO inhibitor (IDOi)-loaded reduced graphene oxide (rGO)-based nanosheets (IDOi/rGO nanosheets) with the properties to directly kill tumor cells under laser irradiation and in situ trigger antitumor immune response. In vivo experiments further revealed that the triggered immune response can be synergistically promoted by IDO inhibition and PD-L1 blockade; the responses included the enhancement of tumor-infiltrating lymphocytes (TILs) including CD45+ leukocytes, CD4+ T cells, CD8+ T cells and NK cells, the inhibition of the immune suppression activity of regulator T cells (Tregs) and the production of INF-γ. We also demonstrate that the three combinations of PTT, IDO inhibition and PD-L1 blockade could effectively inhibit the growth of both irradiated tumors and tumors in distant sites without PTT treatment. This work can be thought as an important proof-of-concept to target multiple antitumor immune pathways to induce synergistic antitumor immunity.
关键词： photothermal therapy,reduced graphene oxide,IDO inhibition,combinatorial immunotherapy,PD-L1
更新于2025-09-23 15:23:52
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Hypoxia-Triggered Transforming Immunomodulator for Cancer Immunotherapy via Photodynamically Enhanced Antigen Presentation of Dendritic Cell
摘要： A key factor for successful cancer immunotherapy (CIT) is the extent of antigen presentation by dendritic cells (DCs) that phagocytize tumor-associated antigens (TAA) in the tumor site and migrate to tumor draining lymph nodes (TDLN), for the activation of T cells. Although various types of adjuvant delivery have been studied to enhance the activity of the DCs, poor delivery efficiency and depleted population of tumor infiltrating DCs have limited the efficacy of CIT. Herein, we report a hypoxia-responsive mesoporous silica nanocarrier (denoted as CAGE) for an enhanced CIT assisted by photodynamic therapy (PDT). In this study, CAGE was designed as a hypoxia-responsive transforming carrier to improve the intracellular uptake of nanocarriers and the delivery of adjuvants to DCs. Furthermore, PDT was exploited for the generation of immunogenic debris and recruitment of DCs in a tumor site, followed by enhanced antigen presentation. Finally, a significant inhibition of tumor growth was observed in vivo, signifying that the PDT would be a promising solution for DC-based immunotherapy.
关键词： combinatorial immunotherapy,hypoxia-responsive drug delivery,tumor-associated antigen,dendritic cell modulation,photodynamic therapy
更新于2025-09-04 15:30:14