Efficient Tumor Eradication Research Articles

Modulation of the Tumor Stroma and Associated Novel Nanoparticle Strategies to Enhance Tumor Targeting

Growth of malignant cells in solid tumors induces changes to the tumor microenvironment (TME). These changes result in promotion of tumor growth, invasion, and metastasis, but also in tumor resistance to drugs and radiotherapy. The enhanced permeability and retention (EPR) effect in neo-angiogenic tumor tissue enables the transport of therapeutic molecules from the circulation into the tumor, but studies show that further diffusion of these agents is often not sufficient for efficient tumor eradication. Despite the hyperpermeable vasculature facilitating the delivery of drugs and tracers, the high density of stromal cells and matrix proteins, in combination with the elevated interstitial fluid pressure in the microenvironment of solid tumors, presents a barrier which limits the delivery of compounds to the core of the tumor. Reversing the cancer-cell-induced changes to the microenvironment as well as novel nanoparticle strategies to circumvent tumor-induced stromal changes have therefore been suggested as potential methods to improve the delivery of therapeutic molecules and drug efficacy. Strategies to modulate the TME, i.e., normalization of tumor vasculature and depletion of excessive stromal proteins and cells, show promising results in enhancing delivery of therapeutic compounds. Modulation of the TME may therefore enhance the efficacy of current cancer treatments and facilitate the development of novel treatment methods as an alternative for invasive resection procedures.

Unlocking the promise of systemic STING agonist for cancer immunotherapy

Stimulator of interferon genes (STING) pathway is the key innate immune pathway involving in cancer immunity. Emerging new molecules and drug delivery systems have made systemic STING agonist immunotherapy possible and demonstrated efficient tumor eradication in preclinical studies. In this perspective, we will discuss the potential mechanisms of STING agonism as a multifaceted anti-cancer therapy and the pharmacological challenges associated with systemic delivery of STING agonists on the level of organs, tissues, cells, and intracellular compartments. We will present and discuss drug delivery strategies to address these challenges. New advances in the field can unlock the promise of systemic STING agonist as effective and safe cancer immunotherapy.

Tumor microenvironment-responsive nanosystem achieves reactive oxygen species self-cycling after photothermal induction to enhance efficacy of antitumor therapy

Tumor microenvironment response and spatio-temporal targeting are promising strategies to combination therapy. By regulating the tumor microenvironment and realizing the precise targeted therapy, the antitumor efficacy can be significantly improved while maintaining low side effects. Therefore, in this study, a reactive oxygen species (ROS)-responsive nanosystem (MND-IR@RESV) was constructed. The MND-IR@RESV nanosystem could be accurately tracked and located due to its own fluorescence. Mitochondria-targeted nanosystem promoted the release of ROS and contributed to the apoptosis of cancer cells. The MND-IR@RESV responded significantly to ROS, which promoted the deep release of drugs. Furthermore, the system also possessed high photothermal conversion efficiency and photothermal stability, which could achieve spatio-temporal targeting of drugs and ensure the efficient tumor eradication ability of Chemo/Photothermal/Photodynamic (CT-PTT-PDT) combination therapy. Both in vitro and in vivo tests demonstrated the significant antitumor effect of the MND-IR@RESV. Importantly, the nanosystem had the advantages of low toxicity and few side effects that conventional CT lacks, indicating that the MND-IR@RESV holds great promise in future cancer treatment.

Nanocomplexes of doxorubicin and DNA fragments for efficient and safe cancer chemotherapy.

Cancer-targeted therapy by a chemotherapeutic agent formulated in a nanoscale platform has been challenged by complex and inefficient manufacturing, low drug loading, difficult characterization, and marginally improved therapeutic efficacy. This study investigated facile-to-produce nanocomplexes of doxorubicin (DOX), a widely used cancer drug, and clinically approved DNA fragments that are extracted from a natural source. DOX was found to self-assemble DNA fragments into relatively monodispersed nanocomplexes with a diameter of ∼70nm at 14.3% (w/w) drug loading by simple and scalable mixing. The resulting DOX/DNA nanocomplexes showed sustained DOX release, unlike overly stable Doxil®, cellular uptake via multiple endocytosis pathways, and high hematological and immunological compatibility. DOX/DNA nanocomplexes eradicated EL4 T lymphoma cells in a time-dependent manner, eventually surpassing free DOX. Extended circulation of DOX/DNA nanocomplexes, while avoiding off-target accumulation in the lung and being cleared from the liver, resulted in rapid accumulation in tumor and lowered cardio toxicity. Finally, tumor growth of EL4-challenged C57BL/6 mice (syngeneic model) and OPM2-challenged NSG mice (human xenograft model) were efficiently inhibited by DOX/DNA nanocomplexes with enhanced overall survival, in comparison with free DOX and Doxil®, especially upon repeated administrations. DOX/DNA nanocomplexes are a promising chemotherapeutics delivery platform for their ease of manufacturing, high biocompatibility, desired drug release and accumulation, efficient tumor eradication with improved safety, and further engineering versatility for extended therapeutic applications.

Metal-coordination synthesis of a natural injectable photoactive hydrogel with antibacterial and blood-aggregating functions for cancer thermotherapy and mild-heating wound repair.

Photothermal therapy (PTT) is a promising approach for treating cancer. However, it suffers from the formation of local lesions and subsequent bacterial infection in the damaged area. To overcome these challenges, the strategy of mild PTT following the high-temperature ablation of tumors is studied to achieve combined tumor suppression, wound healing, and bacterial eradication using a hydrogel. Herein, Bi2S3 nanorods (NRs) are employed as a photothermal agent and coated with hyaluronic acid to obtain BiH NRs with high colloidal stability. These NRs and allantoin are loaded into an injectable Fe3+-coordinated hydrogel composed of sodium alginate (Alg) and Farsi gum (FG), which is extracted from Amygdalus scoparia Spach. The hydrogel can be used for localized cancer therapy by high-temperature PTT, followed by wound repair through the combination of mild hyperthermia and allantoin-mediated induction of cell proliferation. In addition, an outstanding blood clotting effect is observed due to the water-absorbing ability and negative charge of FG and Alg as well as the porous structure of hydrogels. The hydrogels also eradicate infection owing to the local heat generation and intrinsic antimicrobial activity of the NRs. Lastly, in vivo studies reveal an efficient photothermal-based tumor eradication and accelerated wound healing by the hydrogel.

Carbon dots nanophotosensitizers with tunable reactive oxygen species generation for mitochondrion-targeted type I/II photodynamic therapy

Carbon dots (CDs) have emerged as promising nanomaterials for bioimaging-guided photodynamic therapy (PDT). However, designing red-emissive CDs (RCDs) with tunable type I and type II reactive oxygen species (ROS) generation to simultaneously meet PDT applications in aerobic and hypoxic scenarios still remain major challenges. Herein, three types of RCDs with maximum emission at approximately 680 nm are successfully prepared. It is noteworthy that they exhibit the adjustable ROS production with equal superoxide anion (via type I PDT) and incremental singlet oxygen (via type II PDT). Detailed structural and optical characterizations along with theoretical calculation reveal that the unique type I/II ROS formation mainly depends on the core sizes and surface states of RCDs, which determine their identical redox potentials and tapering energy gaps between singlet- and triplet states, respectively. Additionally, due to the inherent mitochondria targeting capability, RCDs enable themselves to induce cell programmed death via activating mitochondrion-mediated apoptotic pathways. This work exploits the unprecedented RCDs with tunable type I and type II ROS generation that could ensure highly efficient tumor eradication both in vitro and in vivo, even under the harsh tumor microenvironment, providing a new prospect for CDs as nanophotosensitizers to conquer the limitations of single type PDT.

Customized tumor antigen delivery by invariant chain to boost T-Cell immunity

Cell-based immunotherapy is one of the wide ranges immunotherapies that especially seeks to generate highly specific T cells targeting tumor cells. Realizing the importance of CD 8+ T cells in eradicating tumor cells, stimulation of the CD 8+ T cells to harvest their cytotoxic capacity has been emphasized. However, it has become more evident that a two dimensional T-cell response involving CD 4+ and CD 8+ T cells is essential for efficient tumor eradication. Continuous effort with various approaches has been adopted to standardize the method of antigen presentation to yield appropriate T-cell response against tumor cells. CLIP modified invariant chain has shown to be able to load the antigen to MHC I molecule. Our current work explains the possibility of activating both CD 4+ and CD 8+ T cells by replacing the CLIP of an invariant chain with a tumor antigen. We have analyzed a public neoantigen created by a frameshift mutation in the TGFβRII gene. The replacement of CLIP by mutated TGFβRII gene allowed it to be loaded to both MHC-I and MHC-II molecule and provided a strong activation of CD 4+ and CD 8+ T cells simultaneously. Further, we investigated the trafficking of such a CLIP replaced invariant chain inside the cell. A transient transfection of CLIP replaced invariant chain construct to MDCK cells revealed its presence in the early and late endosomes suggesting its role in trafficking MHC-I molecule to the endosomes. Essentially our results identified the CLIP region of an invariant chain to be an ideal region to clone the cancer antigen and invariant chain as a potential vector for cancer vaccination. Our in-vitro experiments also suggest that vaccination through a tumor antigen loaded invariant chain can raise specific anti-tumor immune response that is co-orchestrated by both CD 4+ and CD 8+ T cells.

A Porous Bimetallic Au@Pt Core-Shell Oxygen Generator to Enhance Hypoxia-Dampened Tumor Chemotherapy Synergized with NIR-II Photothermal Therapy.

The characteristic hypoxia of solid tumors and inadequate oxygen supply become a key causation of the resistance to chemotherapy in cancer treatment. Herein, a bimetallic oxygen nanogenerator, i.e., porous Au@Pt core-shell nanostructures, is particularly developed to reduce the multidrug resistance by oxygenating the tumor along with synergistic chemo-photothermal therapy for efficient tumor eradication. The porous platinum (Pt) shell was able to catalyze oxygen generation from endogenous hydrogen peroxide in the tumor, reducing the exocytosis of doxorubicin (DOX) via suppressed expression of hypoxia-inducible factor-1α, multidrug resistance gene 1, and P-glycoprotein. The strong absorbance of Au@Pt nanostructures in NIR window II enabled NIR-II photothermal therapy. Further incorporation of DOX into the mesopores of Au@Pt nanostructures with the assistance of phase change materials (PCM) led to the formulation of Au@Pt-DOX-PCM-PEG nanotherapeutics for NIR-II-activated chemotherapy. This work presents an efficient H2O2-driven oxygenerator for enhanced hypoxia-dampened chemotherapy and NIR-II photothermal therapy.

Evaluation of the tumoricidal efficacy of adoptive cell transfer using hepatocellular carcinoma-derived organoids.

Tumor-derived organoid, namely tumoroid, can realistically retain the clinicopathologic features of original tumors even after long-term in vitro expansion. Here we develop this production methodology derived from hepatocellular carcinoma primary samples and generate a platform to evaluate the tumoricidal efficacy of autologous adoptive cell transfer including tumor infiltrating lymphocytes and peripheral blood lymphocytes. Haematoxylin and eosin together with immunohistochemistry staining were employed to ascertain the morphologic and histological features of tumoroids and original tumors. Tumor killing ability of T cells was detected by lactate dehydrogenase assay and propidium iodide staining. In tumoroid xenograft mouse model, tumor volumes were measured and T cell functions were examined by flow cytometry technique. Four tumoroids with characteristics of poor differentiation and mild fibrosis were successfully established from fourteen hepatocellular carcinoma samples. More robust antitumor potential and hyper-functional phenotype of all four tumor infiltrating lymphocytes were observed compared to matched peripheral blood lymphocytes in coculture system. In tumoroid xenograft mouse models, however, only one patient-derived tumor infiltrating lymphocytes with the highest antitumor activity can bestow efficient tumor eradication. Hepatocellular carcinoma tumoroid-based models could represent invaluable resources for evaluating the tumoricidal efficacy of autologous adoptive cell transfer. Tumor infiltrating lymphocytes should be a promising and yet-to-be-developed regimen to treat hepatocellular carcinoma.

An iron oxide nanoparticle-based transdermal nanoplatform for dual-modal imaging-guided chemo-photothermal therapy of superficial tumors

Transdermal delivery is an attractive strategy for treating superficial tumors. However, the applications of existing transdermal systems have been limited by low transdermal efficiency and poor therapeutic outcomes. Here, we develop a transdermal nanoplatform (+)T-SiDs, based on superparamagnetic iron oxide core, surface-modified with cationic lipids, transdermal enhanced peptide TD, and 1,1’-dioctadecyl-3,3,3’,3’-tetramethylindotricarbocyanine iodide (DiR), and loaded with doxorubicin. The (+)T-SiDs compositions enable MR/NIR dual-modal imaging guided synergistic chemo-photothermal therapy to superficial tumors treatment via transdermal delivery. The (+)T-SiDs exhibit good stability, efficient cellular uptake, pH/photothermal responsive drug release, and high photothermal conversion efficiency (47.45%). Importantly, the transdermal delivery of (+)T-SiDs is significantly enhanced by TD functionalization. In vivo MR/NIR imaging shows that the (+)T-SiDs exhibit high transdermal efficiency and specificity in localization to the tumor site. Moreover, in comparison with individual chemo- or photothermal therapies, the combination of chemo-photothermal therapy exhibits more efficient tumor inhibition effects. This work presents a new transdermal treatment nanoplatform for dual-modal imaging-guided chemo-photothermal therapy of superficial tumors, with efficient tumor eradication and low systemic toxicity thus offering strong potential for clinical adoption. Statement of significanceTransdermal delivery is an attractive strategy for treating superficial tumors. However, a highly efficient transdermal nanoplatform remains to be developed. Herein, we designed a multifunctional transdermal nanoplatform for dual-modal imaging-guided chemo-photothermal therapy of superficial tumors, comprised of a super-paramagnetic iron oxide (SPIO) nanoparticle, which can act as an MRI contrast agent and photothermal agent; a transdermal enhanced peptide (TD) and cationic lipids, which can accelerate skin penetration; and a NIR dye (DiR) and doxorubicin (DOX), which can achieve a synergistic enhanced chemo-photothermal therapy with NIR imaging ability. The transdermal nanoplatform achieved efficient tumor eradication and low systemic toxicity, thus offering strong potential for clinical adoption.

Activating Layered Metal Oxide Nanomaterials via Structural Engineering as Biodegradable Nanoagents for Photothermal Cancer Therapy.

Layered metal oxides including MoO3 and WO3 have been widely explored for biological applications owing to their excellent biocompatibility, low toxicity, and easy preparation. However, they normally exhibit weak or negligible near-infrared (NIR) absorption and thus are inefficient for photo-induced biomedical applications. Herein, the structural engineering of layered MoO3 and WO3 nanostructures is first reported to activate their NIR-II absorption for efficient photothermal cancer therapy in the NIR-II window. White-colored micrometre-long MoO3 nanobelts are transformed into blue-colored short, thin, defective, interlayer gap-expanded MoO3-x nanobelts with a strong NIR-II absorption via the simple lithium treatment. The blue MoO3-x nanobelts exhibit a large extinction coefficient of 18.2 L g-1 cm-1 and high photothermal conversion efficiency of 46.9% at 1064nm. After surface modification, the MoO3-x nanobelts can be used as a robust nanoagent for photoacoustic imaging-guided photothermal therapy to achieve efficient cancer cell ablation and tumor eradication under irradiation by a 1064nm laser. Importantly, the biodegradable MoO3-x nanobelts can be rapidly degraded and excreted from body. The study highlights that the structural engineering of layered metal oxides is a powerful strategy to tune their properties and thus boost their performances in given applications.

Nitrogen-containing bisphosphonate-loaded micro-arc oxidation coating for biodegradable magnesium alloy pellets inhibits osteosarcoma through targeting of the mevalonate pathway

Osteosarcoma (OS) remains one of the most threatening primary malignant human tumors of the bone, especially in the first or second decade of life. Unfortunately, the clinical therapeutic efficacy has not substantially improved over the past four decades. Therefore, to achieve efficient tumor eradication, a new approach to prevent tumor recurrence is urgently needed. Here, we develop a new bisphosphonate (BP)-loaded microarc oxidation (MAO) coated magnesium-strontium (Mg-Sr) alloy pellet that can inhibit OS, and we illuminate the cellular and molecular mechanisms of the inhibiting effect. To generate such pellets, nitrogen-containing BP is chemically conjugated with a MAO coating on hollow Mg-Sr alloys. We demonstrate that BP coated Mg pellet has multiple desired features for OS therapy through in vitro and in vivo studies. At the cellular level, BP coated Mg pellets not only induce apoptosis and necrosis, as well as antitumor invasion of OS cells in the two-dimensional (2D) cell culture environment, but also damage the formation of multicellular tumor spheroids by OS cell lines in the three-dimensional (3D) cell culture environment. At the in vivo level, BP coated Mg pellets can destroy tumors and prevent neoplasm recurrence via synergistic Mg degradation and drug release. It is further suggested that the superior inhibitory effect on OS of our pellet is achieved by inhibiting the mevalonate pathway at the molecular level. Hence, these results collectively show that the BP coated Mg pellet is a promising candidate for future applications in repairing defects after tumor removal in OS therapy.

Loss of core fucosylation enhances the anticancer activity of cytotoxic T lymphocytes by increasing PD-1 degradation.

As an immune checkpoint, programmed cell death 1 (PD-1) and its ligand (PD-L1) pathway plays a crucial role in CD8+ cytotoxic T lymphocytes (CTL) activation and provides antitumor responses. The N-glycans of PD-1 and PD-L1 are highly core fucosylated, which are solely catalyzed by the core fucosyltransferase (Fut8). However, the precise biological mechanisms underlying effects of core fucosylation of PD-1 and PD-L1 on CTL activation have not been fully understood. In this study, we found that core fucosylation was significantly upregulated in lung adenocarcinoma. Compared to those of Fut8+/+ OT-I mice, the lung adenocarcinoma formation induced by urethane was markedly reduced in Fut8-/- OT-I mice. De-core fucosylation of PD-1 compromised its expression on Fut8-/- CTL, resulted in enhanced Fut8-/- CTL activation and cytotoxicity, leading to more efficient tumor eradication. Indeed, loss of core fucosylation significantly enhanced the PD-1 ubiquitination and in turn led to the degradation of PD-1 in the proteasome. Our current work indicates that inhibition of core fucosylation is a unique strategy to reduce PD-1 expression for the antilung adenocarcinoma immune therapy in the future.

Therapeutic potential of follicular helper T cells for melanoma treatment

Abstract Clinical relapse and metastases are the major causes of death in melanoma. Currently, adoptive T cell therapy using tumor-infiltrating lymphocytes rich in cytotoxic CD8+ T cells (CTLs) is one of the promising approaches that helps overcome this major challenge in melanoma; however, CTL cell transfer alone does not improve clinical response, suggesting a supportive role of helper CD4+ T cells. There is increasing evidence on the potential contribution of tumor-infiltrated CD4+ T follicular helper (Tfh) cells and intratumoral lymphoid structure formation in tumor eradication; however to date, the role of Tfh cells in anti-tumor immunity has not been clearly elucidated. Remarkably, using a murine melanoma model, we found that the percentage of intratumoral Tfh cells negatively correlates with melanoma growth. In addition, we observed enhanced tumor growth in Bcl6 T-cell conditional knockout mice, which lack Tfh cells as compared to wild-type mice, suggesting that Tfh cells might play a protective role in tumor growth and could serve as a marker for tumor regression. Importantly, in support of mouse studies, in melanoma patients the number of Tfh cells correlate with the rate of patient survival. Importantly, adoptive transfer of antigen specific Tfh cells into tumor bearing mice results in increased number of intratumoral CTLs, as well as in an efficient tumor eradication, indicating the essential role of Tfh cells in promoting CTL expansion and anti-tumor reactivity. Our results thus, for the first time, indicate the therapeutic potential of Tfh cells in promoting CTL-mediated anti-tumor immunity against melanoma and provide the basis for potential usage of these cells to improve current immunotherapy approaches.

Mitochondrion- and nucleus-acting polymeric nanoagents for chemo-photothermal combination therapy

Developing intrinsically mitochondria-targetable nanosystems for subcellular structure-oriented precise cancer therapy is highly desirable. Here, we conjugate the cluster determinant 44 (CD44)-targetable hyaluronic acid (HA) with cholesterol-poly(ethylene glycol)2k-NH2 and mitochondria-acting IR825-NH2 (a cyanine dye) to construct a self-assembled nanostructure (abbreviated as HA-IR825-Chol) for photothermal therapy. The HA-IR825-Chol exhibits improved photostability and desirable photothermal properties, and can rapidly and substantially enter CD44-over-expressed cancer cells and selectively accumulate in the mitochondria of the cells. Upon near-infrared laser irradiation, it can induce severe mitochondrial damage, which causes cytochrome c release and triggers cell apoptosis. Furthermore, we demonstrate the feasibility of loading the chemother-apeutics 10-hydroxycamptothecin (HCPT) into the hydrophobic cores of HA-IR825-Chol NPs for combined chemo-photothermal therapy. HCPT encapsulated within HA-IR825-Chol achieves significantly increased cellular uptake and simultaneous mitochondrial and nuclear localization, leading to the release of cytochrome c from mitochondria and upregulation of cleaved caspase-3, both of which contribute to the cell apop-tosis/death. In vivo experiments reveal the excellent tumor-targeting ability of HA-IR825-Chol/HCPT, ensuring the efficient tumor eradication by the chemo-photothermal therapy. This work exemplifies the development of an intrinsically mitochon-dria-targetable nanocarrier for precise subcellular structure-localized drug delivery, and the Choi-mediated rapid and massive endocytosis of the nanoagents may represent a robust strategy for enhancing the efficacies of nanomedicines.

Function of T follicular helper cells in anti-tumor immunity

Abstract Clinical relapse and metastases are the major causes of death in melanoma. Currently, adoptive T cell therapy using tumor-infiltrating lymphocytes rich in cytotoxic CD8+ T cells (CTLs) is one of the promising approaches that helps overcome this major challenge in melanoma; however CTL cell transfer alone does not improve clinical response suggesting a role of helper CD4+ T cells. Recently, it has been noted that infiltration of a CD4+ T helper subset, named as T follicular helper (Tfh) cells into tumor sites correlates with increased survival of cancer patients; however their role in tumor immunity has not been clearly elucidated till date. In our hands, both pre-clinical murine tumor studies and patient studies show correlation between increased number of intratumoral Tfh cells and reduced melanoma tumor growth and improved survival, suggesting the novel function of Tfh cells in promoting anti-tumor immunity against melanoma. Remarkably, transfer of tumor antigen-specific Tfh cells in melanoma tumor-bearing mice results in increased intratumoral CTL number and function, as well as in more efficient tumor eradication, indicating the role of Tfh cells in antitumor immunity by promoting CTL expansion and/or activity. Moreover, we determined that Tfh derived cytokine interleukin (IL)-21 contributes to intratumoral CTL activity. Our results thus for first time indicate the therapeutic potential of Tfh cells in promoting anti-tumor immunity against melanoma and provide the basis for potential usage of these cells to improve current immunotherapy approaches.

Influence of Retronectin-Mediated T-Cell Activation on Expansion and Phenotype of CD19-Specific Chimeric Antigen Receptor T Cells.

Enhanced in vivo expansion, long-term persistence of chimeric antigen receptor T (CART) cells, and efficient tumor eradication through these cells are linked to the proportion of less-differentiated cells in the CART cell product. Retronectin is well established as an adjuvant for improved retroviral transduction, while its property to enrich less-differentiated T cells is less known. In order to increase these subsets, this study investigated the effects of retronectin-mediated T-cell activation for CD19-specific CART cell production. Peripheral blood mononuclear cells of healthy donors and untreated chronic lymphocytic leukemia (CLL) patients without or with positive selection for CD3+ T cells were transduced with a CD19.CAR.CD28.CD137zeta third-generation retroviral vector. Activation of peripheral blood mononuclear cells was performed by CD3/CD28, CD3/CD28/retronectin, or CD3/retronectin. Interleukin-7 and -15 were supplemented to all cultures. Retronectin was used in all three activation protocols for retroviral transduction. Expansion was assessed by trypan blue staining. Viability, transduction efficiency, immune phenotype, and cytokine production were longitudinally analyzed by flow cytometry. Cytotoxic capacity of generated CART cells was evaluated using a classical chromium-51 release assay. Retronectin-mediated activation resulted in an enrichment of CD8+ cytotoxic CART cells and less-differentiated naïve-like T cells (CD45RA+CCR7+). Retronectin-activated CART cells showed increased cytotoxic activity. However, activation with retronectin decreased viability, expansion, transduction efficiency, and cytokine production, particularly of CLL patient-derived CART cells. Both retronectin-mediated activation protocols promoted a less-differentiated CART cell phenotype without comprising cytotoxic properties of healthy donor-derived CART cells. However, up-front retronectin resulted in reduced viability and expansion in CLL patients. This effect is probably attributed to the retronectin-mediated activation of B cells with prolonged CLL persistence. Consequently, CART cell expansion and generation failed. In summary, activation with retronectin should be performed with caution and may be limited to patients without a higher percentage of tumor cells in the peripheral blood.

Enhancing Osteosarcoma Killing and CT Imaging Using Ultrahigh Drug Loading and NIR-Responsive Bismuth Sulfide@Mesoporous Silica Nanoparticles.

Despite its 5-year event-free survival rate increasing to 60-65% due to surgery and chemotherapy, osteosarcoma (OS) remains one of the most threatening malignant human tumors, especially in young patients. Therefore, a new approach that combines early diagnosis with efficient tumor eradication and bioimaging is urgently needed. Here, a new type of mesoporous silica-coated bismuth sulfide nanoparticles (Bi2 S3 @MSN NPs) is developed. The well distributed mesoporous pores and large surface areas hold great promise for drug protection and encapsulation (doxorubicin (DOX), 99.85%). Moreover, the high photothermal efficiency of Bi2 S3 @MSNs (36.62%) offers great possibility for cancer synergistic treatment and highly near-infrared-triggered drug release (even at an ultralow power density of 0.3 W cm-2 ). After covalently conjugated to arginine-glycine-aspartic acid (RGD) peptide [c(RGDyC)], the NPs exhibit a high specificity for osteosarcoma and finally accumulate in the tumor cells (tenfold more than peritumoral tissues) for computed tomography (CT) imaging and tumor ablation. Importantly, the synergistic photothermal therapy-chemotherapy of the RGD-Bi2 S3 @MSN/DOX significantly ablates the highly malignant OS. It is further proved that the superior combined killing effect is achieved by activating the mitochondrial apoptosis pathway. Hence, the smart RGD-Bi2 S3 @MSN/DOX theranostic platform is a promising candidate for future applications in CT monitoring and synergistic treatment of malignant tumors.

2D Ultrathin MXene-Based Drug-Delivery Nanoplatform for Synergistic Photothermal Ablation and Chemotherapy of Cancer.

Two-dimensional (2D) MXenes, as a new 2D functional material nanosystem, have been extensively explored for broad applications. However, their specific performance and applications in theranostic nanomedicine have still rarely been explored. This work reports on the drug-delivery performance and synergistic therapeutic efficiency of Ti3 C2 MXenes for highly efficient tumor eradication. These Ti3 C2 MXenes not only possess high drug-loading capability of as high as 211.8%, but also exhibit both pH-responsive and near infrared laser-triggered on-demand drug release. Especially, based on the high photothermal-conversion capability of Ti3 C2 MXenes, they have been further explored for efficient tumor eradication by synergistic photothermal ablation and chemotherapy, which has been systematically demonstrated both in vitro and in vivo. These Ti3 C2 MXenes have also been demonstrated as the desirable contrast agents for photoacoustic imaging, showing the potential for diagnostic-imaging guidance and monitoring during therapy. The high in vivo histocompatibility of Ti3 C2 and their easy excretion out of the body have been evaluated and demonstrated, showing the potential high biosafety for further clinical translation. This work paves a new way for broadening biomedical applications of MXenes in nanomedicine where they can exert the high performance and functionality for synergistic therapy, especially on combating cancer.

Blockage of Core Fucosylation Reduces Cell-Surface Expression of PD-1 and Promotes Anti-tumor Immune Responses of T Cells

Programmed cell death 1 (PD-1) is highly expressed on exhausted Tcells and inhibits Tcell activation. Antibodies that block the interaction between PD-1 and its ligand prevent this inhibitory signal and reverse Tcell dysfunction, providing beneficial anti-tumor responses in a substantial number of patients. Mechanisms for the induction and maintenance of high PD-1 expression on exhausted Tcells have not been fully understood. Utilizing a genome-wide loss-of-function screening method based on the CRISPR-Cas9 system, we identified genes involved in the core fucosylation pathway as positive regulators of cell-surface PD-1 expression. Inhibition of Fut8, a core fucosyltransferase, by genetic ablation or pharmacologic inhibition reduced cell-surface expression of PD-1 and enhanced Tcell activation, leading to more efficient tumor eradication. Taken together, our findings suggest that blocking core fucosylation of PD-1 can be a promising strategy for improving anti-tumor immune responses.