Ablation Of Tumor Cells Research Articles

Rational design of AIEgens through π-bridge engineering for dual-modal photodynamic and photothermal therapy.

A series of aggregation-induced emission luminogens (AIEgens) with donor-π-acceptor (D-π-A) architecture were rationally designed and synthesized through π-bridge engineering for dual-modal photodynamic and photothermal therapy. The AIEgens (TPT, TFT, and TTT) were constructed using methoxy-substituted tetraphenylene as the electron donor and tricyanofuran as the electron acceptor, connected via different π-bridges (phenyl, furan, or thiophene). These compounds exhibited red-shifted absorption (460-545nm) and emission (712-720nm) with remarkable aggregation-induced emission characteristics. Among them, TTT demonstrated superior photophysical properties and was successfully encapsulated into amphiphilic calixarene-based nanoparticles (T@Q NPs) with uniform morphology. The T@Q NPs showed efficient reactive oxygen species generation and photothermal conversion (η=6.98%), enabling effective tumor cell ablation through combined photodynamic and photothermal therapy. In vivo studies revealed that T@Q NPs achieved 70% tumor growth inhibition in 4T1 tumor-bearing mice without obvious systemic toxicity. This work presents an effective strategy for designing AIEgens-based phototherapeutic agents through π-bridge engineering, offering promising candidates for clinical translation in tumor phototherapy.

Biodegradable Vanadium-Based Nanomaterials for Photothermal-Enhanced Tumor Ferroptosis and Pyroptosis.

The designability and high reactivity of nanotechnology provide strategies for antitumor therapy by regulating the redox state in tumor cells. Here, we synthesize a kind of vanadium dioxide nanoparticle encapsulated in bovine serum albumin and containing disulfide bonds (VSB NPs) for photothermal-enhanced ferroptosis and pyroptosis effects. Mechanism studies show that disulfide bonds can effectively consume overexpressed glutathione (GSH) in the tumor microenvironment, leading to a decrease in glutathione peroxidase 4 (GPX4) activity. Simultaneously, tetravalent vanadium can induce a catalytic reaction of overexpressed H2O2, producing plenty of toxic hydroxyl radicals (·OH) and singlet oxygen (1O2), leading to tumor cell ferroptosis. In addition, the consumption of disulfide bonds can also lead to the degradation of nanoparticles into high-valent vanadates, activating thermal protein domain-associated protein 3 (NLRP3) inflammasomes and causing tumor cell pyroptosis. It is worth mentioning that VSB NPs can not only ablate tumor cells under near-infrared light irradiation but also further disrupt the redox homeostasis of the tumor microenvironment, thereby enhancing the ferroptosis and pyroptosis of tumor cells induced by biodegradable vanadium-based nanomaterials. This strategy, based on the biological effects of vanadium to regulate the redox state in tumor cells, provides possibilities for cancer treatment.

Multifunctional Thermoelectric Nanocatalysts for Synergistic Uveal Melanoma Treatment by Specific Cuproptosis and Pyroptosis

AbstractUveal melanoma (UM) is a highly aggressive ocular malignancy associated with a poor prognosis and significant resistance to conventional therapies, including surgical resection, chemotherapy, and radiotherapy, which are often limited by their efficacy and adverse side effects. Energy‐conversion‐based nanodynamic therapy, which facilitates the generation of reactive oxygen species (ROS), has emerged as a promising approach for cancer treatment. Here, the development of high‐performance multifunctional thermoelectric nanocatalysts, specifically Cu5FeS3.6Se0.4 nanoparticles, optimized for the effective synergistic treatment of UM is reported. These nanoparticles exhibit remarkable photothermal, thermoelectric, and chemodynamic properties that enhance therapeutic efficacy. Under near‐infrared light irradiation, Cu5FeS3.6Se0.4 nanoparticles generate localized hyperthermia, which not only induces direct tumor cell ablation but also produces thermoelectric potentials that facilitate ROS generation. Additionally, the hyperthermia induced by the photothermal effects of these nanoparticles accelerates a Fenton‐like reaction, leading to the formation of highly reactive hydroxyl radicals for chemodynamic therapy. The resultant ROS induce oxidative stress within tumor cells, promoting mechanisms such as cuproptosis and pyroptosis. The integration of photothermal effects, thermoelectric potentials, and chemodynamic therapy within a single nanoplatform represents an efficient strategy for UM treatment, addressing the shortcomings of traditional therapies and offering a highly effective means of managing this aggressive cancer.

Tumor-derived extracellular vesicles disrupt the blood–brain barrier endothelium following high-frequency irreversible electroporation

High-frequency irreversible electroporation (H-FIRE), a nonthermal brain tumor ablation therapeutic, generates a central tumor ablation zone while transiently disrupting the peritumoral blood–brain barrier (BBB). We hypothesized that bystander effects of H-FIRE tumor cell ablation, mediated by small tumor-derived extracellular vesicles (sTDEV), disrupt the BBB endothelium. Monolayers of bEnd.3 cerebral endothelial cells were exposed to supernatants of H-FIRE or radiation (RT)-treated LL/2 and F98 cancer cells. Endothelial cell response was evaluated microscopically and via flow cytometry for apoptosis. sTDEV were isolated following H-FIRE and RT, characterized via nanoparticle tracking analysis (NTA) and transmission electron microscopy, and applied to a Transwell BBB endothelium model to quantify permeability changes. Supernatants of H-FIRE-treated tumor cells, but not supernatants of sham- or RT-treated cells, disrupted endothelial cell monolayer integrity while maintaining viability. sTDEV released by glioma cells treated with 3000 V/cm H-FIRE increased permeability of the BBB endothelium model compared to sTDEV released after lower H-FIRE doses and RT. NTA revealed significantly decreased sTDEV release after the 3000 V/cm H-FIRE dose. Our results demonstrate that sTDEV increase permeability of the BBB endothelium after H-FIRE ablation in vitro. sTDEV-mediated mechanisms of BBB disruption may be exploited for drug delivery to infiltrative margins following H-FIRE ablation.

Magnetic Induction Heating in a Conducting Polymer for Biomedical Applications.

In this study, we investigate the magnetic induction heating induced in a conducting polymer (CP) under alternative magnetic fields (AMFs). Experimental results and numerical simulations have proved that the magneto-thermal conversion of the CP is caused by the induced eddy current, which is related to the shape and intensity of the applied external AMF, and the intrinsic electrical conductivity, macrostructure and microstructure of the CP. By employing various fabrication methods, specific temperature distribution and control of thermal field within conducting polymer films and aerogels could be achieved. To exploit the potential of magnetic induction heating in CP for biomedical applications, we designed a conducting polymer aerogel-based self-adaptive heat patch and demonstrated its AMF-enabled localized heating of skin. In addition to the thermal ablation of tumor cells via magneto-thermal conversion of the CP, the promotion of neuronal differentiation at mild temperature by noninvasive magneto-electrical stimulation has also been demonstrated to be an effective strategy for tissue engineering.

A cell membrane-targeted photosensitizer for cancer photodynamic therapy and dynamic ablation process tracking

Photodynamic therapy (PDT) uses photosensitizer (PS) to generate reactive oxygen species (ROS) under light to trigger cell apoptosis in cancer treatment. Organelle-targeted PS can effectively enhance the efficacy of phototherapy by specifically destroying subcellular organelles. The cell membrane, as an important organelle, is the “protective wall” of cells maintaining the integrity and normal life activities of cells. The damage to cell membranes is fatal to cells. However, utilizing functional PS to achieve cell membrane-targeted PDT, and realize real-time and accurate in situ reporting of cell membrane damage and monitoring of the treatment process, are challenging tasks. In this work, we prepared a photosensitizer (2TPAO) with aggregation-induced emission (AIE) characteristics, good water solubility, strong near-infrared fluorescence, and the capability for specific imaging of cell membranes. Moreover, 2TPAO could effectively produce ROS under visible light irradiation and achieve photodynamic ablation of tumor cells and tumors. Meanwhile, during PDT, the fluorescence changes of 2TPAO indicated the destruction of cell membranes, allowing intuitive determination of the phototherapy results. Therefore, 2TPAO is an effective cell membrane-targeted PS for cancer PDT.

A Chemotherapy-Photothermal synergistic system in bifunctional bone Scaffold: Tumor therapy and bone repair

Bone defect repair and tumor recurrence are the main challenges in the postoperative treatment of bone tumors. The incorporation of zoledronate (ZOL) into scaffolds presents a promising approach, attributed to its osteogenic and anti-tumor properties. However, there are still some unfavorable factors that make it difficult to eradicate tumor cells at the surgical site, including drug rapid release, the insufficient anti-tumor efficacy of ZOL and the multidrug resistance of chemotherapy. Herein, a novel nano drug delivery platform mesoporous silicon-coated graphene oxide (GO/MSN) and ZOL loaded nanoparticle (GO/MSN-ZOL) were developed. Then PLLA/ GO/MSN-ZOL scaffold that integrates photothermal therapy (PTT) and chemotherapy was fabricated using poly (L-lactic acid) as raw materials by selective laser sintering (SLS) technology. The GO not only imparted scaffold with photothermal properties for localized tumor cell ablation but also significantly enhanced its anti-tumor efficacy through synergistic effects in combination with chemotherapy. The mesoporous structure and large specific surface area of MSN contribute to the sustained release of ZOL. Additionally, GO could promote osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), which in combine with ZOL’s osteoclast inhibition, enhances the bone repair capacity. This study offers a straightforward and promising strategy for treating tumor-related bone defects.

Tumor Metabolism Aiming Cu2-xS Nanoagents Mediate Photothermal-Derived Cuproptosis and Immune Activation.

Cuproptosis is an emerging form of cell death that relies on the targeted delivery of copper ions to lipoylated tricarboxylic acid cycle proteins. However, a major challenge associated with cuproptosis is its potential to kill both normal and tumor cells without discrimination. Therefore, it is crucial to develop strategies for precise intracellular delivery and redox control of copper to create effective cuproptosis-based tumor therapies. We have introduced a class of nanoagents called metabolism aiming Cu2-xS (MACuS) through a glucose-mediated biomineralization approach. MACuS nanoagents can be specifically targeted to tumors via the glucose transport receptor 1, and we found that NIR-II irradiation can not only result in direct hyperthermia ablation of tumor cells but also facilitate efficient cuproptosis and enhance reactive oxygen species-induced cytotoxicity in tumor cells. As a result, the triple effect of MACuS treatment induced immunogenic cell death, which triggered systemic antitumor immune responses and demonstrated potent efficacy in inhibiting growth, metastasis, and recurrence in mouse and rabbit breast cancer models. The precise intracellular delivery and redox control of copper provided by MACuS hold great potential for the development of highly efficient cuproptosis-based tumor therapies with minimal off-target effects.

Cascade STING activation of a ternary immunostimulant for colorectal cancer eradication via photodynamic DNA damage and T regulatory cell inhibition

Stimulator of interferon genes (STING) plays an essential role in initiating the innate anti-tumor immunity, which could be activated by the cytosolic DNA but suppressed by the immunosuppressive cells. In this work, a self-delivery ternary immunostimulant (designated as ImmSt) is fabricated for colorectal cancer therapy with the immunological cascades of photodynamic DNA damage and T regulatory cell inhibition. Among which, the photosensitizer of Chlorin e6 (Ce6), the STING agonist of 5,6-dimethylxanthine-4-acetic acid (DMXAA) and the phosphatidylinositol 3-kinases (PI3Ks) inhibitor of ZSTK474 could self-assemble into uniform nanomedicine without drug excipient, which enhances the drug stability, bioavailability and pharmacological activities. Importantly, the photodynamic therapy (PDT) effect of ImmSt produces enormous reactive oxygen species to ablate tumor cells, and also triggers the release of cytosolic DNA to amplify the STING signal in combination with the STING agonist. Moreover, ImmSt is able to induce a systemic anti-tumor immunity by the cascade activation of T cells and the decrease of T regulatory cells. In vitro and in vivo results confirm that ImmSt can efficiently eradicate colorectal cancer without severe side effects, which may provide a sophisticated mechanism for immunotherapy in consideration of the immune activation and immunosuppressive factors.

Illuminating the fight against breast cancer: Preparation and visualized photothermal therapy of hyaluronic acid coated ZIF-8 loading with indocyanine green and cryptotanshinone for triple-negative breast cancer

Triple-negative breast cancer (TNBC) is characterized by higher recurrence rate and mortality. Thermally-mediated ablation via photothermal therapy (PTT) demonstrates considerable promise for the eradication of breast cancer. Nonetheless, the efficacy of PTT is impeded by the thermal tolerance of tumor cells, which is attributed to the augmented expression of heat shock proteins (HSPs). These proteins, which function as ATP-dependent molecular chaperones, confer protection to cancer cells against the cytotoxic heat generated during PTT. Glycolysis is an important way for breast cancer cells to produce ATP, which can promote the occurrence and development of lung metastasis of breast cancer. Therefore, inhibiting glycolysis may diminish the expression of HSPs, curtail the growth of breast cancer, and prevent its metastasis. Glycolytic metabolism plays a pivotal role in the ATP biosynthesis within breast cancer cells, facilitating the progression and dissemination of pulmonary metastases. Consequently, targeting glycolysis presents a strategic approach to HSP expression, the proliferation of breast cancer, and impede its metastatic spread. Herein, we designed an indocyanine green (ICG) and cryptotanshinone (CTS) loaded hyaluronic acid (HA) coated Zeolitic Imidazolate Framework-8 (ZIF-8) drug delivery system. The drug delivery system had excellent photothermal properties, which could reach temperature sufficient for photothermal ablation of tumor cells. (ICG + CTS)@HA-ZIF-8 also showed pH-responsive drug release, enhancing the sustained release of ICG and CTS to extend their systemic circulation duration. Moreover, the HA modification of ZIF-8 served to augment its targeting capabilities both in vitro and in vivo, leveraging the enhanced permeation and retention (EPR) effect, as well as active tumor targeting via the CD44 receptor pathway, resulting in a higher drug concentration and a better therapeutic effect in tumor. (ICG + CTS)@HA-ZIF-8 could downregulate the expression of glycolysis-related protein pyruvate kinase-M2 (PKM2), thereby inhibiting the glycolysis process, further suppressing tumor cell energy metabolism, downregulating the expression of HSPs, overcoming tumor cell heat resistance, and improving PTT effect. It exhibited a notable suppressive impact on both the proliferation and migration of breast cancer cells, potentially offering innovative insights for the visualized PTT in breast cancer treatment.

Acoustic waves and smart biomimetic nanoparticles: combination treatment from 2D to 3D colorectal cancer models

Colorectal Cancer (CRC) is the second leading cause of death among tumors worldwide. Conventional treatments are often accompanied by emerging immunotherapies, trying to reduce the burden of advanced and metastatic stages. Recently, nanomedicine therapies have been under intensive research to offer new perspectives to patients. Motivated by this rationale, this work proposes the formulation of advanced biomimetic and targeted nanoparticles (NPs) enabling a stimuli responsive and localized therapy, triggered by the safe use of acoustic shockwaves, a deep-penetrating tissue stimulation. Iron-doped zinc oxide nanocrystals were synthetized and enveloped in a biomimetic lipid bilayer shell, conjugating a peptide (YSA) as selective targeting toward CRC cells. Comparative studies, performed both in 2D monolayer and 3D spheroids of CRC models, between non-targeted (L-ZnO) and targeted (YSA-L-ZnO) nanoparticles demonstrated the superior capability of targeted nanosystems to dock and be internalized by CRC cells. The YSA-L-ZnO are proven to be highly biocompatible and hemocompatible, and capable of inducing selective damage, once activated by safe shockwaves. This mechanism is able to synergistically ablate tumor cells in both 2D and 3D models, proofing the concept of an innovative stimuli-responsive nanomedicine with a targeted and biomimetic strategy to offer future options for cancer fight.Graphical

Preparation of environmentally responsive PDA&DOX@LAC live drug carrier for synergistic tumor therapy

The development of intelligent, environmentally responsive and biocompatible photothermal system holds significant importance for the photothermal combined therapy of tumors. In this study, inspired by Lactobacillus (LAC), we prepared a biomimetic nanoplatform PDA&DOX@LAC for tumor photothermal-chemotherapy by integrating the chemotherapeutic drug doxorubicin (DOX) with dopamine through oxidative polymerization to form polydopamine (PDA) on the surface of LAC. The PDA&DOX@LAC nanoplatform not only achieves precise and controlled release of DOX based on the slightly acidic microenvironment of tumor tissues, but also exhibits enzyme-like properties to alleviate tumor hypoxia. Under near-infrared light irradiation, it effectively induces photothermal ablation of tumor cells, enhances cellular uptake of DOX with increasing temperature, and thus efficiently inhibits tumor cell growth. Moreover, it is further confirmed in vivo experiments that photothermal therapy combined with PDA&DOX@LAC induces tumor cells apoptosis, releases tumor-associated antigens, which is engulfed by dendritic cells to activate cytotoxic T lymphocytes, thereby effectively suppressing tumor growth and prolonging the survival period of 4T1 tumor-bearing mice. Therefore, the PDA&DOX@LAC nanoplatform holds immense potential in precise tumor targeting as well as photothermal combined therapy and provides valuable insights and theoretical foundations for the development of novel tumor treatment strategies based on endogenous substances within the body.

Nanoparticles Encapsulated in Red Blood Cell Membranes for Near-Infrared Second Window Imaging-Guided Photothermal-Enhanced Immunotherapy on Tumors.

Photothermal therapy (PTT), which uses the high thermal conversion ability of photothermal agents to ablate tumor cells at high temperatures, has gained significant attention because it has the advantages of high selectivity and specificity, precise targeting of tumor sites, and low invasiveness and trauma. However, PTT guided by the NIR-I has limitations in tissue penetration depth, resulting in limited imaging monitoring and therapeutic effects on deep-seated tumor tissues. Moreover, nanoparticles are easily cleared by the immune system and difficult to passively target tumor sites during the process of treatment. To address these issues, we prepared nanoparticles using NIR-II dyes IR1048 and DSPE-PEG-OH and further encapsulated them in red blood cell membranes derived from mice. These biomimetic nanoparticles, called RDIR1048, showed reduced clearance by the immune system and had long circulation characteristics. They effectively accumulated at tumor sites, and strong fluorescence could still be observed at the tumor site 96 h after administration. Furthermore, through mouse thermal imaging experiments, we found that RDIR1048 exhibited good PTT ability. When used in combination with an immune checkpoint inhibitor, anti-PD-L1 antibodies, it enhanced the immunogenic cell death of tumor cells caused by PTT and improved the therapeutic effect of immunotherapy, which demonstrated good therapeutic efficacy in the treatment of tumor-bearing mice. This study provides a feasible basis for the future development of NIR-II nanoparticles with long circulation properties.

Black TiO2-based nanoparticles as Toll-like receptor stimulator delivery system for enhanced photothermal-immunotherapy of pancreatic cancer

BackgroundThe tumor-specific immune responses, essential for removing residual lesions and preventing tumor metastases, can be stimulated by tumor-associated antigens (TAAs) released following photothermal therapy (PTT). However, due to the immunosuppressed microenvironment of pancreatic ductal adenocarcinoma (PDAC), the TAAs released by PTT are difficult to induce an effective immune response. In this work, we prepared the mesoporous silica (mSiO2) coated black titanium dioxide (bTiO2) photothermal nanoparticles (NPs) for enhanced photothermal-immunotherapy toward PDAC, in which resiquimod (R848) was loaded and DOTA-Gd was conjugated. The NPs are specified as bTiO2@mSiO2@Gd/R848 and abbreviated to NPs/R848. R848 as a kind of Toll-like receptor 7/8 agonist can remodel the tumor microenvironment (TME) in PDAC and induce a strong immune response. Furthermore, DOTA-Gd serves as a magnetic resonance imaging (MRI) contrast agent to improve the T1-weighted MRI performance of the NPs.ResultsIn vitro results of this study show that NPs/R848 could thermally ablate tumor cells and efficiently trigger dendritic cell (DC) maturation. The results of in vivo investigations demonstrate that the combined use of photothermal-immunotherapy exhibits a significant inhibitory effect on tumor growth. Besides, it promoted maturation of DCs and enhanced infiltration of CD8 + , CD4 + T cells to improve the TME in PDAC.ConclusionsOur study anticipates that by encouraging the maturation of DCs, this strategy will improve the TME and enable the successful photothermal-immunotherapy of PDAC.

A narrow-bandgap RuI3 nanoplatform to synergize radiotherapy, photothermal therapy, and thermoelectric dynamic therapy for tumor eradication

Therapeutic resistance is an essential challenge for nanotherapeutics. Herein, a narrow bandgap RuI3 nanoplatform has been constructed firstly to synergize radiotherapy (RT), photothermal therapy (PTT), and thermoelectric dynamic therapy (TEDT) for tumor eradication. Specifically, the photothermal performance of RuI3 can ablate tumor cells while inducing TEDT. Noteworthy, the thermoelectric effect is found firstly in RuI3, which can spontaneously generate an electric field under the temperature gradient, prompting carrier separation and triggering massive ROS generation, thus aggravating oxidative stress level and effectively inhibiting HSP-90 expression. Moreover, RuI3 greatly enhances X-ray deposition owing to its high X-ray attenuation capacity, resulting in a pronounced computed tomography imaging contrast and DNA damage. In addition, RuI3 possesses both catalase-like and glutathione peroxidase-like properties, which alleviate tumor hypoxia and reduce antioxidant resistance, further exacerbating 1O2 production during RT and TEDT. This integrated therapy platform combining PTT, TEDT, and RT significantly inhibits tumor growth. Statement of significanceRuI3 nanoparticles were synthesized for the first time. RuI3 exhibited the highest photothermal properties among iodides, and the photothermal conversion efficiency was 53.38 %. RuI3 was found to have a thermoelectric effect, and the power factor could be comparable to that of most conventional thermoelectric materials. RuI3 possessed both catalase-like and glutathione peroxidase-like properties, which contributed to enhancing the effect of radiotherapy.

Synthesis and application of multifunctional magnetic mesoporous nanomaterials with redox reaction and NIR response in tumor treatment

In recent years, the novel minimally invasive combination therapy for tumors has garnered widespread attention due to its controllable therapeutic target, effective combination therapy outcome, and minimal toxic side effects. This study integrated inorganic nanospheres of ferric oxide (Fe3O4) with mesoporous silica nanoparticles (MSN), along with polymeric organic polymers—polyaniline (PANI) and hyaluronic acid (HA)—to create a multifunctional tumor treatment platform (Fe3O4@MSN@PANI@HA), aiming to enhance the efficacy of therapies that have monotherapy limitations. The Fe2+ within the Fe3O4@MSN@PANI@HA nanoparticles can react with the unique hydrogen peroxide present in the tumor microenvironment to generate hydroxyl radicals (·OH), which possess cytotoxic properties that can selectively eradicate tumor cells, thereby facilitating chemodynamic therapy (CDT). Moreover, Fe3O4@MSN@PANI@HA nanoparticles, when loaded with the chemotherapy drug doxorubicin hydrochloride (DOX), yield Fe3O4@MSN@PANI@HA-DOX nanoparticles. It has been demonstrated that these nanoparticles exhibit commendable drug-loading efficiency and controlled drug-release capabilities, contributing to the chemotherapy of tumors. The inclusion of PANI in the Fe3O4@MSN@PANI@HA nanoparticles endows them with an exceptional photothermal conversion capability. Upon exposure to an 808-nm near-infrared laser (NIR), the photothermal conversion efficiency of the composite nanomaterials reaches 42.76 %, thereby enabling photothermal therapy (PTT) through the thermal ablation of tumor cells. The HA component of the composite nanoparticles provides excellent biocompatibility and a sustained drug-release effect. Simultaneously, it could target tumor cells by recognizing specific receptors that are overexpressed on the cell surfaces, directing the transport of the composite nanoparticles to the tumor site, and selectively destroying tumor cells. This paper confirms the potent therapeutic impact of composite nanoparticles on tumors and offers a novel perspective for designing multifunctional composite nanomaterials.

Synchronized Chemotherapy/Photothermal Therapy/Sonodynamic Therapy of Human Triple-Negative and Estrogen Receptor-Positive Breast Cancer Cells Using a Doxorubicin–Gold Nanoclusters–Albumin Nanobioconjugate

ObjectiveNovel strategies for treating triple-negative breast cancer (TNBC) are ongoing because of the lack of standard-of-care treatment. Nanoframed materials with a protein pillar are considered a valuable tool for designing multigoals of energy-absorbing/medication cargo and are a bridge to cross-conventional treatment strategies. MethodsNanobioconjugates of gold nanoclusters–bovine serum albumin (AuNCs–BSA) and doxorubicin–AuNCs–BSA (Dox–AuNCs–BSA) were prepared and employed as a simultaneous double photosensitizer/sonosensitizer and triple chemotherapeutic/photosensitizer/sonosensitizer, respectively. ResultsThe highly stable AuNCs–BSA and Dox–AuNCs–BSA have ζ potentials of –29 and –18 mV, respectively, and represent valuable photothermal and sonodynamic activities for the combination of photothermal therapy and sonodynamic therapy (PTT/SDT) and synchronized chemotherapy/photothermal therapy/sonodynamic therapy (CTX/PTT/SDT) of human TNBC cells, respectively. The efficiency of photothermal conversion of AuNCs–BSA was calculated to be a promising value of 32.9%. AuNCs–BSA and Dox–AuNCs–BSA were activated on either laser light irradiation or ultrasound exposure with the highest efficiency on the combination of both types of radiation. CTX/PTT/SDT of MCF-7 and MDA-MB-231 breast cancer cell lines by Dox–AuNCs–BSA were evaluated with the MTT cell proliferation assay and found to progress synergistically. ConclusionResults of the MTT assay, detection of the generation of intracellular reactive oxygen species and occurrence of apoptosis in the cells confirmed that CTX/PTT/SDT by Dox–AuNCs–BSA was attained with lower needed doses of the drug and improved tumor cell ablation, which would result in the enhancement of therapeutic efficacy and overcoming of therapeutic resistance.

Abstract 6531: Anti-tumor immune function of NR2F6, an orphan nuclear receptor, in stromal cells

Abstract Growing evidence points to the importance of the tumor microenvironment (TME) in tumor growth control, progression, and therapy response. Among those is the greater understanding of immune system components within the TME as mediators of tumor growth control. NR2F6 is an orphan nuclear receptor, which was shown to serve as an immune intrinsic checkpoint component and has been suggested to elicit tumor-intrinsic suppression of anti-tumor immunity. Correspondingly, genetic depletion of NR2F6 in CD8 T cells abrogates the immune-activating cytokines (e.g., IL-2, IFNg). In addition, genetic ablation of NR2F6 in melanoma cells activates CD8 T cell-mediated anti-tumor immunity partly by suppressing the expression of tumor-intrinsic immune repressors NACC1 and FKBP10. Notably, combined genetic ablation of tumor cells (NR2F6 KO melanoma) and stroma cells (NR2F6 KO mouse) resulted in a more pronounced inhibition of tumor growth compared with ablation of either tumor cells or TME. The latter provides the foundation for screening NR2F6 inhibitors, which are expected to have a strong systemic (tumor inhibition and immune cell activation) effect on tumor growth. Interestingly, single-cell transcriptomic data from human tumors identified high expression of NR2F6 in stroma cells, cancer-associated fibroblasts (CAFs), and tumor-associated endothelial cells (TAEs). Consistent with these, scRNAseq analysis of mouse melanoma revealed higher expression of NR2F6 in SMA+ immune suppressive myo-CAFs than in immune activating CAFs. Studies that directly reveal the role of stromal NR2F6 in anti-tumor immunity and tumor growth and the state of NR2F6 inhibitors will be discussed. Citation Format: Hyungsoo Kim, Yongmei Feng, Marria Radaeva, Eduard Sergienko, Artem Cherkasov, Ze'ev A. Ronai. Anti-tumor immune function of NR2F6, an orphan nuclear receptor, in stromal cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6531.

Ti2C3 MXene-based nanocomposite as an intelligent nanoplatform for efficient mild hyperthermia treatment

Photothermal therapy (PTT) has attracted much attention due to its less invasive, controllable and highly effective nature. However, PTT also suffers from intrinsic cancer resistance mediated by cell survival pathways. These survival pathways are regulated by a variety of proteins, among which heat shock protein (HSP) triggers thermotolerance and protects tumor cells from hyperthermia-induced apoptosis. Confronted by this challenge, we propose and validate here a novel MXene-based HSP-inhibited mild photothermal platform, which significantly enhances the sensitivity of tumor cells to heat-induced stress and thus improves the PPT efficacy. The Ti3C2@Qu nanocomposites are constructed by utilizing the high photothermal conversion ability of Ti3C2 nanosheets in combination with quercetin (Qu) as an inhibitor of HSP70. Qu molecules are loaded onto the nanoplatform in a pH-sensitive controlled release manner. The acidic environment of the tumor causes the burst-release of Qu molecules, which deplete the level of heat shock protein 70 (HSP70) in tumor cells and leave the tumor cells out from the protection of the heat-resistant survival pathway in advance, thus sensitizing the hyperthermia efficacy. The nanostructure, photothermal properties, pH-responsive controlled release, synergistic photothermal ablation of tumor cells in vitro and in vivo, and hyperthermia effect on subcellular structures of the Ti3C2@Qu nanocomposites were systematically investigated.

Glutathione degradable manganese-doped polydopamine nanoparticles for photothermal therapy and cGAS-STING activated immunotherapy of lung tumor

Photothermal therapy (PTT), which utilizes nanomaterials to harvest laser energy and convert it into heat to ablate tumor cells, has been rapidly developed for lung tumor treatment, but most of the PTT-related nanomaterials are not degradable, and the immune response associated with PTT is unclear, which leads to unsatisfactory results of the actual PTT. Herein, we rationally designed and prepared a manganese ion-doped polydopamine nanomaterial (MnPDA) for immune-activated PTT with high efficiency. Firstly, MnPDA exhibited 57.2% photothermal conversion efficiency to accomplish high-efficiency PTT, and secondly, MnPDA can be stimulated by glutathione (GSH) to the release of Mn2+, and it can produce ·OH in a Fenton-like reaction with the overexpressed H2O2 and stimulate the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. These two synergistically can effectively remove lung tumor cells that have not been ablated by PTT, resulting in an 86.7% tumor suppression rate under laser irradiation of MnPDA in vivo, and further significantly activated the downstream immune response, as evidenced by an increased ratio of cytotoxic T cells to immunosuppressive Treg cells. Conclusively, the GSH degradable MnPDA nanoparticles can be used for photothermal therapy and cGAS-STING-activated immunotherapy of lung tumors, which provides a new idea and strategy for the future treatment of lung tumors.