Multi-Functional AIE Phototheranostic Agent Enhancing αPD-L1 Response for Oral Squamous Cell Carcinoma Immunotherapy.

Oral squamous cell carcinoma (OSCC) represents a prevalent head and neck malignancy with surgical intervention as the primary clinical option. Immunotherapy, particularly immune checkpoint blockade (ICB) targeting PD-1/PD-L1 shows great promise but is impeded by the immunosuppressive tumor microenvironment and low PD-L1 expression in OSCC. Herein, the "all-in-one" phototherapeutic nanoparticles (TSD NPs) are reported with balanced reactive oxygen species and photothermal conversion capacity for combined photoimmunotherapy and ICB immunotherapy against OSCC. A novel electron acceptor, 3-(dicyanomethylene)-2,3-dihydrobenzothiophene-1,1-dioxide (DTM), is introduced to develop the phototherapeutic agent with aggregation-induced emission (AIE) feature and NIR-II fluorescence centered at 1000 nm. Benefiting from the AIE feature and the DTM acceptor, the resultant TSD NPs also exhibit strong type I reactive oxygen species (ROS) generation and high photothermal conversion efficiency (45.3%), which can profoundly induce immunogenic cell death (ICD), activate cytotoxic T lymphocytes, and convert the immunosuppressive tumor microenvironment into an immune-supportive one. Additionally, TSD NPs upregulate the PD-L1 expression on OSCC cells, thus enhancing the efficacy of combined treatment with αPD-L1 ICB immunotherapy. This results show that the synergistic treatment of TSD NPs and αPD-L1 effectively eradicates solid OSCC tumors without adverse effects on normal tissues, proving a novel and promising strategy for OSCC management.

Engineered photonic near-infrared light activated photothermal theranostic nanovaccine induced targeted remodeling of tumor microenvironment.

Tumor recurrence, which happens as a result of persisting tumor cells and minor lesions after treatments like surgery and chemotherapy, is a major problem in oncology. Herein, a strategy to combat this issue by utilize a theranostic nanovaccine composed of photonic HCuS. This nanovaccine aims to eradicate cancer cells and their traces while also preventing tumor recurrence via optimizing the photothermal immune impact. Successful membrane targeting allows for the introduction of new therapeutic agents into the tumor cells. Together with co-encapsulated Toll-Like Receptors (TLR7/8) agonist R848 for activating T cells and maturing DCs, the combined effects of HCuS and ICG function as photothermal agents that generate heat in the presence of NIR light. Photothermal-mediated immunotherapy with therapeutic modalities proved successful in killing tumor cells. By activating the immune system, this new photonic nanovaccine greatly increases immunogenic cell death (ICD), kills tumor cells, and prevents their recurrence.

Molecular Engineering of NIR-II/IIb Emitting AIEgen for Multimodal Imaging-Guided Photo-Immunotherapy.

In view of the great challenges related to the complexity and heterogeneity of tumors, efficient combination therapy is an ideal strategy for eliminating primary tumors and inhibiting distant tumors. A novel aggregation-induced emission (AIE) phototherapeutic agent called T-TBBTD is developed, which features a donor-acceptor-donor (D-A-D) structure, enhanced twisted molecule conformation, and prolonged second near-infrared window (NIR-II) emission. The multimodal imaging function of the molecule has significance for its treatment time window and excellent photothermal/photodynamic performance for multimode therapy. The precise molecular structure and versatility provide prospects for molecular therapy for anti-tumor applications. Fluorescence imaging in the NIR-II window offers advantages with enhanced spatial resolution, temporal resolution, and penetration depth. The prepared AIE@R837 NPs also have controllable performance for antitumor photo-immunotherapy. Following local photo-irradiation, AIE@R837 NPs generate abundant heat, and 1 O2 directly kills tumor cells, induces immunogenic cell death (ICD) as a photo-therapeutic effect, and releases R837, which enhances the synergistic effect of antigen presentation and contributes to the long-lasting protective antitumor immunity. A bilateral 4T1 tumor model revealed that this photo-immunotherapy can eliminate primary tumors. More importantly, it has a significant inhibitory effect on distant tumor growth. Therefore, this method can provide a new strategy for tumor therapy.

Nanodrug Inducing Autophagy Inhibition and Mitochondria Dysfunction for Potentiating Tumor Photo-Immunotherapy.

Anticancer immunotherapy is hampered by the poor tumor immunogenicity and immunosuppressive tumor microenvironment (TME). Herein, a liposome nanodrug co-encapsulating doxycycline hydrochloride (Doxy) and chlorin e6 (Ce6) to simultaneously induce autophagy inhibition and mitochondria dysfunction for potentiating tumor photo-immunotherapy is developed. Under near infrared laser irradiation, Ce6 generates cytotoxic reactive oxygen species (ROS) and elicits robust photodynamic therapy (PDT)-induced immunogenic cell death (ICD) for immunosuppressive TME remodeling. In addition, Doxy induced mitochondria dysfunction, which increases ROS generation and enhances PDT to exert more potent killing effect and more powerful ICD. Meanwhile, Doxy increases MHC-I expression on tumor cells surface by efficient autophagy inhibition, leading to more efficient antigen presentation and CTLs recognition to increase tumor immunogenicity. The nanodrugs elicit remarkable antitumor therapy by combining Ce6-mediated PDT and Doxy-induced autophagy inhibition and mitochondria dysfunction. The developed nanodrugs represent a highly efficient strategy for improving cancer immunotherapy.

Nanotheranostic Trojan Horse for visualization and photo-immunotherapy of multidrug-resistant bacterial infection.

Effective diagnosis and therapy for bacterial infections, especially those caused by multidrug-resistant (MDR) species, greatly challenge current antimicrobial stewardship. Monocytes, which can chemotactically migrate from the blood to infection site and elicit a robust infection infiltration, provide a golden opportunity for bacterial theranostics. Here, a nano-Trojan Horse was facilely engineered using mannose-functionalized manganese-eumelanin coordination nanoparticles (denoted as MP-MENP) for precise two-step localization and potent photothermal-immunotherapy of MDR bacterial infection. Taking advantage of the selective recognition between mannose and inflammation-associated monocytes, the MP-MENP could be passively piggybacked to infection site by circulating monocytes, and also actively target infiltrated monocytes that are already accumulated in infection microenvironment. Such dual-pronged targeting enabled an efficient imaging diagnosis of bacterial infection. Upon laser irradiation, the MP-MENP robustly produced local hyperemia to ablate bacteria, both extracellularly and intracellularly. Further combined with photothermal therapy-induced immunogenic cell death and MP-MENP-mediated macrophage reprogramming, the immunosuppressive infection microenvironment was significantly relieved, allowing an enhanced antibacterial immunity. Collectively, the proposed nanotheranostic Trojan Horse, which integrates dual-pronged targeting, precise imaging diagnosis, and high-performance photothermal immunotherapy, promises a new way for complete eradication of MDR bacterial infection.

Light-triggered multifunctional nanoplatform for efficient cancer photo-immunotherapy.

Cancer immunotherapy is limited by the immune escape of tumor cells and adverse effects. Photo-immunotherapy, the combination of immunotherapy and phototherapy (such as photodynamic therapy (PDT) and photothermal therapy (PTT)), can improve the effectiveness of immunotherapy in cancer treatment. Here, we first explored mesoporous hexagonal core-shell zinc porphyrin-silica nanoparticles (MPSNs), which are composed of a zinc porphyrin core and a mesoporous silica shell, and exhibit high laser-triggered photodynamic and photothermal activity, as well as outstanding drug loading capacity. In other words, MPSNs can be used not only as excellent photosensitizers for photo-immunotherapy, but also as an ideal drug carrier to achieve more efficient synergy. After loading with R837 (imiquimod, a toll-like receptor-7 agonist), MPSNs@R837 will elicit high-efficiency immunogenic cell death via PDT and PTT, and promote dendritic cell maturation after the PH-responsive release of R837, thereby, inducing tumor-specific immune responses. When combined with a programmed death ligand-1 checkpoint blockade, the photo-immunotherapy system markedly restrains primary tumors and metastatic tumors with negligible systemic toxicity. Therefore, the therapeutic strategy of integrating PTT, PDT and checkpoint blockade, shows great potential for suppressing cancer metastasis.

Photosynthetic Microorganisms-Based Biophotothermal Therapy with Enhanced Immune Response.

The production of oxygen by photosynthetic microorganisms (PSMs) has recently attracted interest concerning the in vivo treatment of multiple diseases for their photosynthetic oxygen production in vivo, since PSMs have good biological safety. Here, the first evidence that PSMs can be used as a photothermal source to perform biophotothermal therapy (bio-PTT) is provided. In vitro and in vivo experiments proved that PSMs can generate heat for the direct elimination of tumors and release a series of pathogen-associated molecular patterns and adjuvants for immune stimulation under light irradiation. Bio-PTT enabled a local tumor inhibition rate exceeding 90% and an abscopal tumor inhibition rate exceeding 75%. This strategy also produced a stronger antitumor immune memory effect to prevent tumor recurrence. The bio-PTT strategy provides a novel direction for photothermal therapy as it simultaneously produces local and abscopal antitumor effects.

Enhancing Anti-PD-1/PD-L1 Immune Checkpoint Inhibitory Cancer Therapy by CD276-Targeted Photodynamic Ablation of Tumor Cells and Tumor Vasculature.

Antiangiogenic therapies have been demonstrated to improve the efficacy of immune checkpoint inhibition by overcoming the immunosuppressive status of the tumor microenvironment. However, most of the current antiangiogenic agents cannot discriminate tumor angiogenesis from physiological angiogenesis. The aim of this study was to investigate whether a photodynamic therapy (PDT) agent that targets CD276, a receptor overexpressed in various tumor cells and tumor vasculature but with limited expression in normal tissue vasculature, could improve the tumor inhibitory efficacy of a PD-1/PD-L1 blockade. A CD276-targeting agent (IRD-αCD276/Fab) was synthesized by conjugating the Fab fragment of an anti-CD276 antibody with a photosensitizer IRDye700. The in vivo tumor-targeting efficacy and therapeutic effects of IRD-αCD276/Fab with or without an anti-PD-1/PD-L1 blockade were tested in subcutaneous and lung metastatic tumor models. PDT using IRD-αCD276/Fab significantly suppressed the growth of subcutaneous 4T1 tumor and inhibited its lung metastasis. Moreover, it triggered in vivo antitumor immunity by increasing the activation and maturation of dendritic cells. Tumor PD-L1 levels were also markedly increased after PDT using IRD-αCD276/Fab, as evidenced by noninvasive PD-L1-targeted small-animal PET imaging. In combination with an anti-PD-1/PD-L1 blockade, IRD-αCD276/Fab PDT markedly suppressed the growth of tumors and prevented their metastasis to the lung by recruiting the tumor infiltration of CD8+ T cells. Our data provide evidence for the role of CD276-targeted PDT for local immune modulation, and its combination with PD-L1/PD-1 axis inhibition is a promising strategy for eliminating primary tumors as well as disseminated metastases, by generating local and systemic antitumor responses.

Cupid and Psyche system for the diagnosis and treatment of advanced cancer.

In advanced cancer patients, malignant cells invade and disseminate within normal cells and develop resistance to therapy with additional genetic mutations, which makes radical cure very difficult. Precision medicine against advanced cancer is hampered by the lack of systems aimed at multiple target molecules within multiple loci. Here, we report the development of a versatile diagnostic and therapeutic system for advanced cancer, named the Cupid and Psyche system. Based on the strong non-covalent interaction of streptavidin and biotin, a low immunogenic mutated streptavidin, Cupid, and a modified artificial biotin, Psyche, have been designed. Cupid can be fused with various single-chain variable fragment antibodies and forms tetramer to recognize cancer cells precisely. Psyche can be conjugated to a wide range of diagnostic and therapeutic agents against malignant cells. The Cupid and Psyche system can be used in pre-targeting therapy as well as photo-immunotherapy effectively in animal models supporting the concept of a system for precision medicine for multiple targets within multiple loci.

Photoimmunotherapy for cancer treatment based on organic small molecules: Recent strategies and future directions.

Photodynamic therapy (PDT) is considered as a promising anticancer approach, owning to its high efficiency and spatiotemporal selectivity. Ample evidence indicated that PDT can trigger immunogenic cell death by releasing antigens that activate immune cells to promote anti-tumor immunity. Nevertheless, the inherent nature of tumors and their complex heterogeneity often limits the efficiency of PDT, which can be overcome with a novel strategy of photo-immunotherapy (PIT) strategy. By exploring the principles of PDT induction and ICD enhancement, combined with other therapies such as chemotherapy or immune checkpoint blockade, the tailored solutions can be designed to address specific challenges of drug resistance, hypoxic conditions, and tumor immunosuppressive microenvironments (TIMEs), which enables targeted enhancement of systemic immunity to address most distant and recurrent cancers. The present article summarizes the specific strategies of PIT and discusses recent existing limitations. More importantly, we anticipate that the perspectives presented herein will help address the clinical translation challenges associated with PIT.