Three-dimensional Tumor Models Research Articles

Extreme transport of light in spheroids of tumor cells

Extreme waves are intense and unexpected wavepackets ubiquitous in complex systems. In optics, these rogue waves are promising as robust and noise-resistant beams for probing and manipulating the underlying material. Localizing large optical power is crucial especially in biomedical systems, where, however, extremely intense beams have not yet been observed. We here discover that tumor-cell spheroids manifest optical rogue waves when illuminated by randomly modulated laser beams. The intensity of light transmitted through bio-printed three-dimensional tumor models follows a signature Weibull statistical distribution, where extreme events correspond to spatially-localized optical modes propagating within the cell network. Experiments varying the input beam power and size indicate that the rogue waves have a nonlinear origin. We show that these nonlinear optical filaments form high-transmission channels with enhanced transmission. They deliver large optical power through the tumor spheroid, and can be exploited to achieve a local temperature increase controlled by the input wave shape. Our findings shed light on optical propagation in biological aggregates and demonstrate how nonlinear extreme event formation allows light concentration in deep tissues, paving the way to using rogue waves in biomedical applications, such as light-activated therapies.

Advances in three-dimensional tumor models for colorectal cancer

Conventional tumor culture models include two-dimensional tumor cell cultures and xenograft models. The former has disadvantages including lack of tumor heterogeneity and poor clinical relevance, while the latter are limited by the slow growth, low engraftment successful rate, and high cost. In recent years, in vitro three-dimensional (3D) tumor models have emerged as the tool to better recapitulate the spatial structure and the in vivo environment of tumors. In addition, they preserve the pathological and genetic features of tumor cells and reflect the complex intracellular and extracellular interactions of tumors, which have become a powerful tool for investigating the tumor mechanism, drug screening, and personalized cancer treatment. 3D tumor model technologies such as spheroids, organoids, and microfluidic devices are maturing. Application of new technologies such as co-culture, 3D bioprinting, and air-liquid interface has further improved the clinical relevance of the models. Some models recapitulate the tumor microenvironment, and some can even reconstitute endogenous immune components and microvasculature. In recent years, some scholars have combined xenograft models with organoid technology to develop matched in vivo/in vitro model biobanks, giving full play to the advantages of the two technologies, and providing an ideal research platform for individualized precision therapy for specific molecular targets in certain subtypes of tumors. So far, the above technologies have been widely applied in the field of colorectal cancer research. Our research team is currently studying upon the application of patient-derived tumor cell-like clusters, a self-assembly 3D tumor model, in guiding the selection of postoperative chemotherapy regimens for colorectal cancer. A high modeling success rate and satisfactory results in the drug screening experiments have been achieved. There is no doubt that with the advancement of related technologies, 3D tumor models will play an increasingly important role in the research and clinical practice of colorectal cancer.

3D Porous Scaffold-Based High-Throughput Platform for Cancer Drug Screening.

Natural polymer-based porous scaffolds have been investigated to serve as three-dimensional (3D) tumor models for drug screening owing to their structural properties with better resemblance to human tumor microenvironments than two-dimensional (2D) cell cultures. In this study, a 3D chitosan-hyaluronic acid (CHA) composite porous scaffold with tunable pore size (60, 120 and 180 µm) was produced by freeze-drying and fabricated into a 96-array platform for high-throughput screening (HTS) of cancer therapeutics. We adopted a self-designed rapid dispensing system to handle the highly viscous CHA polymer mixture and achieved a fast and cost-effective large-batch production of the 3D HTS platform. In addition, the adjustable pore size of the scaffold can accommodate cancer cells from different sources to better mimic the in vivo malignancy. Three human glioblastoma multiforme (GBM) cell lines were tested on the scaffolds to reveal the influence of pore size on cell growth kinetics, tumor spheroid morphology, gene expression and dose-dependent drug response. Our results showed that the three GBM cell lines showed different trends of drug resistance on CHA scaffolds of varying pore size, which reflects the intertumoral heterogeneity across patients in clinical practice. Our results also demonstrated the necessity to have a tunable 3D porous scaffold for adapting the heterogeneous tumor to generate the optimal HTS outcomes. It was also found that CHA scaffolds can produce a uniform cellular response (CV < 0.15) and a wide drug screening window (Z' > 0.5) on par with commercialized tissue culture plates, and therefore, can serve as a qualified HTS platform. This CHA scaffold-based HTS platform may provide an improved alternative to traditional 2D-cell-based HTS for future cancer study and novel drug discovery.

Novel 3D Custom-Made Silicone Tumor Model as a Support for Teaching Surgical Oncology Principles.

Alternative laboratory teaching methods are becoming increasingly desirable and effective in medical education environments. While ethical concerns associated with the use of live animals in terminal surgery laboratories have been reduced with cadaveric models, availability, and lack of pathology can limit their ability to adequately convey surgical principles and replicate clinical training. We have developed a three-dimensional (3D) custom-made silicone soft tissue tumor model using 3D-printed molds derived from canine soft tissue sarcoma computed tomography images. This novel teaching model allows users to apply surgical oncology principles and perform basic technical tasks such as incisional biopsy, margin demarcation, marginal and wide surgical excision, and inking of surgical margins. A large cohort of students in addition to a small number of professional veterinarians at different levels of specialty training followed the laboratory guidelines and evaluated the simulated tumor model based on a qualitative survey. All participants were able to successfully complete the practical training. The model also allowed the students to identify and correct technical errors associated with biopsy sampling and margin dissection, and to understand the clinical impacts related to those errors. Face and content validity of the model were assessed using Likert-style questionnaires with overall average instructors' scores of 3.8/5 and 4.6/5, respectively. Content validity assessment of the model by the students approximated instructors' evaluation with an overall average score of 4.4/5. This model development emphasizes the efficacy of alternative non-cadaveric laboratory teaching tools and could become a valuable aid in the veterinary curricula.

Robust formation of optimal single spheroids towards cost-effective in vitro three-dimensional tumor models.

While useful for fundamental in vitro studies, monolayer cell cultures are not physiologically relevant. Spheroids, a complex three-dimensional (3D) structure, more closely resemble in vivo tumor growth. Spheroids allow the results obtained relating to proliferation, cell death, differentiation, metabolism, and various antitumor therapies to be more predictive of in vivo outcomes. In the protocol herein, a rapid and high-throughput method is discussed for the generation of single spheroids using various cancer cell lines, including brain cancer cells (U87 MG, SEBTA-027, SF188), prostate cancer cells (DU-145, TRAMP-C1), and breast cancer cells (BT-549, Py230) in 96-round bottom-well plates. The proposed method is associated with significantly low costs per plate without requiring refining or transferring. Homogeneous compact spheroid morphology was evidenced as early as 1 day after following this protocol. Proliferating cells were traced in the rim, while dead cells were found to be located inside the core region of the spheroid using confocal microscopy and the Incucyte® live imaging system. H&E staining of spheroid sections was utilized to investigate the tightness of the cell packaging. Through western blotting analyses, it was revealed that a stem cell-like phenotype was adopted by these spheroids. This method was also used to obtain the EC50 of the anticancer dipeptide carnosine on U87 MG 3D culture. This affordable, easy-to-follow five-step protocol allows for the robust generation of various uniform spheroids with 3D morphology characteristics.

A transformable three-dimensional simulated solid tumor model reveals the widespread killing potential of natural killer cells with controlled lytic granule positioning

Abstract Cancer immunotherapy using engineered natural killer (NK) cells has shown great promise. However, the limited spatial complexity of current models hinders the study of NK cells in three-dimensional, solid tumor-like environments. Previously, we found that NK cells converge lytic granules before degranulation. It helps focus the secretion of cytotoxic cargos to the synaptic cleft, thus preventing the non-specific killing of bystander cells. We had speculated that bypassing this protective mechanism and forcing NK cells to degranulate non-directionally may promote broader destruction of cancer cells and eradicate tumor-resident non-triggering cells. To evaluate our hypothesis, we designed a novel strategy for creating complex cellular environments with controlled spatial distribution and intercellular dynamics. Using hydrogel-embedded cells as building blocks, we construct 3D models that arrange multiple cell populations within desired inner structures. Notably, these structures can undergo controlled transformations enabled by hydrogels comprised of thermo-responsive polymers. During this transformation, cells experienced rapid but mechanically gentle translocation to pre-designated positions, allowing us to control cell contacts actively. With these systems (which we have termed TheCOS for Thermal Collapse Of Strata), we observed that controlling NK cell lytic granule positioning at a lytic immune synapse was able to promote bystander cell death within a complex multicellular environment. Using quantitative imaging, we calculated an area of damage attributable to radial degranulation, which suggests a potential benefit to this as a strategy for improving cytotoxic cell therapy for solid tumors.

Proteolytically degradable PEG hydrogel matrix mimicking tumor immune microenvironment for 3D co-culture of lung adenocarcinoma cells and macrophages

Tumor-associated macrophages and monocytes are the major stromal cell types found in the tumor immune microenvironment (TIME), which modulates tumor progression, invasion, and chemoresistance. To address the need for an in vitro three-dimensional tumor model for understanding the complex cellular interactions within the TIME, we propose a TIME-mimetic co-culture matrix composed of photo-crosslinked poly(ethylene glycol) hydrogels mimicking the characteristics of the tumor and stroma. Desmoplasia-mimetic microgels encapsulating lung adenocarcinoma cells (A549) were embedded with monocyte- or macrophage-type U937 cells in normal stroma-mimetic hydrogel, increasing the proximity between the two cell types. By modulating the proteolytic degradability of the hydrogels, we could separate different cell types with high purities for use in orthogonal assays. In addition, we demonstrated that U937 cells had distinct influences on A549 cell death depending on their activation states (i.e. monocyte, M0, or M1 phenotype). M1 macrophages suppressed tumor growth and increased the susceptibility of A549 cells to cisplatin. In contrast, monocytes upregulated cancer stem cell markers (OCT4, SOX2, and SHH) of A549 cells, showing M2-like features, such as downregulated expression of proinflammatory markers (IL6 and TNFα). These findings suggest that this co-culture system is potentially used for investigation of heterotypic cellular interactions in the TIME.

3D Tumor Models in Urology.

Three-dimensional tumor models have become established in both basic and clinical research. As multicellular systems consisting of tumor and tumor-associated cells, they can better represent tumor characteristics than monocellular 2D cultures. In this review, we highlight the potential applications of tumor spheroids and organoids in the field of urology. Further, we illustrate the generation and characteristics of standardized organoids as well as membrane-based 3D in vitro models in bladder cancer research. We discuss the technical aspects and review the initial successes of molecular analyses in the three major urologic tumor entities: urinary bladder carcinoma (BCa), prostate carcinoma (PCa), and renal cell carcinoma (RCC).

Functional biomaterials for biomimetic 3D in vitro tumor microenvironment modeling

The translational potential of promising anticancer medications and treatments may be enhanced by the creation of 3D in vitro models that can accurately reproduce native tumor microenvironments. Tumor microenvironments for cancer treatment and research can be built in vitro using biomaterials. Three-dimensional in vitro cancer models have provided new insights into the biology of cancer. Cancer researchers are creating artificial three-dimensional tumor models based on functional biomaterials that mimic the microenvironment of the real tumor. Our understanding of tumor stroma activity over the course of cancer has improved because of the use of scaffold and matrix-based three-dimensional systems intended for regenerative medicine. Scientists have created synthetic tumor models thanks to recent developments in materials engineering. These models enable researchers to investigate the biology of cancer and assess the therapeutic effectiveness of available medications. The emergence of biomaterial engineering technologies with the potential to hasten treatment outcomes is highlighted in this review, which also discusses the influence of creating in vitro biomimetic 3D tumor microenvironments utilizing functional biomaterials. Future cancer treatments will rely much more heavily on biomaterials engineering.

Cellular migration in IDH-wildtype glioblastoma: a case series on the genomics of amoeboid movement and its prognostic significance

Glioblastoma is an aggressive, fatal form of adult diffuse glioma. The ability of glioblastoma cells to switch to an amoeboid-like mode of invasion contributes greatly to tumour aggressiveness,1 though the prognostic value of genes related to amoeboid migration are not well characterised. Aims: To explore genes involved in amoeboid-related events (AREs) and determine differences in the frequency of genomic alterations between different adult glioma subgroups. Methods: An extensive literature review was conducted to identify genes involved in AREs. The genomic alteration frequency of identified ARE-associated genes were compared between low and high-grade glioma cohorts (LGG and HGG, respectively), stratified by their IDH1/2 mutation status. The prognostic significance of ARE-genes was also analysed using the HGG cohort. Results: Overall, 273 genes related to AREs were identified and subtyped. ARE-associated genomic alterations were significantly more common in IDH-mutant HGG, relative to IDH-wildtype HGG (p=0.048). Survival analyses indicated that novel ARE-associated genes, PIK3R6, PLA2G2F, PLA2G4B, PLA2G4F, PNPLA3, ARPC4 and WNT8A, may have prognostic value in HGG patients. Of interest, MAP2K2, was associated with longer overall survival in HGG patients. Conclusion: ARE-associated genes show varying genomic alterations between different adult glioma subtypes and represent an exciting opportunity for further investigation. Reference 1. Koh I, Cha J, Park J, et al. The mode and dynamics of glioblastoma cell invasion into a decellularized tissue-derived extracellular matrix-based three-dimensional tumor model. Sci Rep 2018; 8: 4608.

Sericultural By-Products: The Potential for Alternative Therapy in Cancer Drug Design

Major progress has been made in cancer research; however, cancer remains one of the most important health-related burdens. Sericulture importance is no longer limited to the textile industry, but its by-products, such as silk fibroin or mulberry, exhibit great impact in the cancer research area. Fibroin, the pivotal compound that is found in silk, owns superior biocompatibility and biodegradability, representing one of the most important biomaterials. Numerous studies have reported its successful use as a drug delivery system, and it is currently used to develop three-dimensional tumor models that lead to a better understanding of cancer biology and play a great role in the development of novel antitumoral strategies. Moreover, sericin's cytotoxic effect on various tumoral cell lines has been reported, but also, it has been used as a nanocarrier for target therapeutic agents. On the other hand, mulberry compounds include various bioactive elements that are well known for their antitumoral activities, such as polyphenols or anthocyanins. In this review, the latest progress of using sericultural by-products in cancer therapy is discussed by highlighting their notable impact in developing novel effective drug strategies.

Current approaches to assessing the biological activity of immunocytokines &lt;i&gt;in vitro&lt;/i&gt;

The use of cytokines as anticancer drugs is limited due to their toxicity. It is possible to reduce toxicity and to increase the therapeutic index by using cytokines in the form of conjugates with antibodies – immunocytokines. The results of preclinical studies have shown increased efficacy and reduced toxicity of various immunocytokines compared to the original, unconjugated cytokines. The potential of immunocytokines as anticancer agents is currently being studied in clinical trials. The therapeutic efficacy of immunocytokines depends on their physicochemical parameters, which determine the in vivo biodistribution, and biological activity as a result of the mechanisms of the antibody action and cytokine sites incorporated in the design. There is a need for methods that allow to assess the biological activity of both individual sites and the entire immunocytokine molecule when characterizing immunocytokines at an early stage of research.This review considers the existing approaches for assessing the biological activity of immunocytokines in vitro in the course of preclinical studies, such as monolayer cultures, reporter cell lines, co-cultures, three-dimensional (3D) tumor models. Monolayer cultures are sufficient to confirm the mechanism of action of separate sites of immunocytokines used in the design, and the “gold standard” test systems for determining the specific biological activity of the cytokine and the effector functions of the antibody site remain in demand. Commercial reporter cell lines remain an alternative option for assessing the biological activity of cytokine and antibody sites at the level of activation of signaling pathways. Co-cultures of tumor and effector cells make it possible to evaluate the cytotoxic and immunomodulatory effects of antibody and cytokine sites without using 3D cultivation methods. The use of 3D tumor models makes it possible to replace several tests for the biological activity of separate sites of immunocytokines conducted on monolayer cultures and co-cultures with one comprehensive study, however, such models require significant time and material costs.

A 3D bioprinted tumor model fabricated with gelatin/sodium alginate/decellularized extracellular matrix bioink.

109Tissue-engineered scaffolds are more commonly used to construct three-dimensional (3D) tumor models for in vitro studies when compared to the conventional two-dimensional (2D) cell culture because the microenvironments provided by the 3D tumor models closely resemble the in vivo system and could achieve higher success rate when the scaffolds are translated for use in pre-clinical animal model. Physical properties, heterogeneity, and cell behaviors of the model could be regulated to simulate different tumors by changing the components and concentrations of materials. In this study, a novel 3D breast tumor model was fabricated by bioprinting using a bioink that consists of porcine liver-derived decellularized extracellular matrix (dECM) with different concentrations of gelatin and sodium alginate. Primary cells were removed while extracellular matrix components of porcine liver were preserved. The rheological properties of biomimetic bioinks and the physical properties of hybrid scaffolds were investigated, and we found that the addition of gelatin increased hydrophilia and viscoelasticity, while the addition of alginate increased mechanical properties and porosity. The swelling ratio, compression modulus, and porosity could reach 835.43 ± 130.61%, 9.64 ± 0.41 kPa, and 76.62 ± 4.43%, respectively. L929 cells and the mouse breast tumor cells 4T1 were subsequently inoculated to evaluate biocompatibility of the scaffolds and to form the 3D models. The results showed that all scaffolds exhibited good biocompatibility, and the average diameter of tumor spheres could reach 148.52 ± 8.02 μm on 7 d. These findings suggest that the 3D breast tumor model could serve as an effective platform for anticancer drug screening and cancer research in vitro.

Magnetic torque–driven living microrobots for increased tumor infiltration

Biohybrid bacteria-based microrobots are increasingly recognized as promising externally controllable vehicles for targeted cancer therapy. Magnetic fields in particular have been used as a safe means to transfer energy and direct their motion. Thus far, the magnetic control strategies used in this context rely on poorly scalable magnetic field gradients, require active position feedback, or are ill-suited to diffuse distributions within the body. Here, we present a magnetic torque-driven control scheme for enhanced transport through biological barriers that complements the innate taxis toward tumor cores exhibited by a range of bacteria, shown for Magnetospirillum magneticum as a magnetically responsive model organism. This hybrid control strategy is readily scalable, independent of position feedback, and applicable to bacterial microrobots dispersed by the circulatory system. We observed a fourfold increase in translocation of magnetically responsive bacteria across a model of the vascular endothelium and found that the primary mechanism driving increased transport is torque-driven surface exploration at the cell interface. Using spheroids as a three-dimensional tumor model, fluorescently labeled bacteria colonized their core regions with up to 21-fold higher signal in samples exposed to rotating magnetic fields. In addition to enhanced transport, we demonstrated that our control scheme offers further advantages, including the possibility for closed-loop optimization based on inductive detection, as well as spatially selective actuation to reduce off-target effects. Last, after systemic intravenous injection in mice, we showed significantly increased bacterial tumor accumulation, supporting the feasibility of deploying this control scheme clinically for magnetically responsive biohybrid microrobots.

Establishment and large-scale validation of a three-dimensional tumor model on an array chip for anticancer drug evaluation.

Two-dimensional (2D) tumor model has always poorly predicted drug response of animal model due to the lack of recapitulation of tumor microenvironment. Establishing a biomimetic, controllable, and cost-effective three-dimensional (3D) model and large-scale validation of its in vivo predictivity has shown promise in bridging the gap between the 2D tumor model and animal model. Here, we established a matrigel-based 3D micro-tumor model on an array chip for large-scale anticancer drug evaluation. Compared with the 2D tumor model, the 3D tumor model on the chip showed spheroid morphology, slower proliferation kinetics, and comparable reproducibility. Next, the results of the chemotherapeutic evaluation from 18 drugs against 27 cancer cell lines showed 17.6% of drug resistance on the 3D tumor model. Moreover, the evaluation results of targeted drugs showed expected sensitivity and higher specificity on the 3D tumor model compared with the 2D model. Finally, the evaluation results on the 3D tumor model were more consistent with the in vivo cell-derived xenograft model, and excluded 95% false-positive results from the 2D model. Overall, the matrigel-based 3D micro-tumor model on the array chip provides a promising tool to accelerate anticancer drug discovery.

Quantum Dots Mediated Imaging and Phototherapy in Cancer Spheroid Models: State of the Art and Perspectives.

Quantum Dots (QDs) are fluorescent nanoparticles known for their exceptional optical properties, i.e., high fluorescence emission, photostability, narrow emission spectrum, and broad excitation wavelength. These properties make QDs an exciting choice for bioimaging applications, notably in cancer imaging. Challenges lie in their ability to specifically label targeted cells. Numerous studies have been carried out with QDs coupled to various ligands like peptides, antibodies, aptamers, etc., to achieve efficient targeting. Most studies were conducted in vitro with two-dimensional cell monolayers (n = 8902) before evolving towards more sophisticated models. Three-dimensional multicellular tumor models better recapitulate in vivo conditions by mimicking cell-to-cell and cell-matrix interactions. To date, only few studies (n = 34) were conducted in 3D in vitro models such as spheroids, whereas these models could better represent QDs behavior in tumors compared to monolayers. Thus, the purpose of this review is to present a state of the art on the studies conducted with Quantum Dots on spheroid models for imaging and phototherapy purposes.

Development of Experimental Three-Dimensional Tumor Models to Study Glioblastoma Cancer Stem Cells and Tumor Microenvironment.

Glioblastoma (GBM) is the most common and dismal primary brain tumor. Unfortunately,despite multidisciplinary treatment, most patients will perish approximately 15months after diagnosis. For this reason, there is an urgent need to improve our understanding of GBM tumor biology and develop novel therapies that can achieve better clinical outcomes. In this setting, three-dimensional tumor models have risen as more appropriate preclinical tools when compared to traditional cell cultures, given that two-dimensional (2D) cultures have failed to accurately recapitulate tumor biology and translate preclinical findings into patient benefits. Three-dimensional cultures using neurospheres, organoids, and organotypic better resemble original tumor genetic and epigenetic profiles, maintaining tumor microenvironment characteristics and mimicking cell-cell and cell-matrix interactions. This chapter summarizes our methods to generate well-characterized glioblastoma neurospheres, organoids, and organotypics.

Susceptibility artifacts evaluation for non-metallic biopsy needles in a biological-engineered 3D tumor model

Abstract Nowadays, needle artifacts are an essential restriction for MRI-guided interventions, as they influence the visually perceived needle size and needle destination. Standard MRI needles made of Nickel-Titanium (NiTi) alloys still produce massive artifacts in MRI due to materials’ interactions with the magnetic environment. The use of non-metallic materials can reduce these artifacts. Therefore, we propose a nonmetallic concept of a coaxial needle design concept with a fiber-enforced inner core and an outer polymeric hollow sheet. This work aims to evaluate the artifact performance of the proposed needles in a custom-made three-dimensional (3D) tumor model with a relevant size and thickness for medical interventions under MRI guidance using a 3T field strength with a T1-weighted gradient-echo sequence. Three coaxial MRcompatible needles were inserted in the custom-made 3D tissue phantom, one standard needle from NiTi, and two proposed non-metallic needles. Artifact’s width and length were measured for each needle. Overall, the non-metallic needles showed significantly lower artifacts than the standard NiTi needle inside the 3D tumor model.

Computational investigation of the tumor position and ambient conditions on magnetic nanoparticle thermo-therapy

• Estimation of effects of tumor position beneath the skin on magnetic nanoparticle hyperthermia (MNPH). • Estimation of effects of therapeutic environmental conditions on MNPH. • Quantification of thermal damage in tumor as well healthy tissues in diverse therapeutic environmental conditions. • Estimation of the critical depth of the tumor up to which the variations in the therapeutic effects of MNPH are significant. The present study elucidate the effects of tumor position and clinical environmental conditions on the therapeutic effects of magnetic nanoparticle hyperthermia (MNH) in superficial like breast tumor tissue. Effects of these two factors are investigated through a three-dimensional (3D) tumor model. The position of the tumor tissue (of size 1.5 cm) within the 3D model as well as the heat transfer rate through the skin is altered to evaluate their effects on MNH. Six different positions of tumor ranging from zero-depth to the tumor depth of 1.5 times the tumor size from the skin are considered. Similarly, three different heat transfer coefficients ( h c = 2.5, 5.5, 7.5 W / m 2 K ) on the skin during thermotherapy are considered to simulate a wide range of clinical environmental conditions. MNH is induced for 1 hour using two different heating powers (with amplitudes of 10 k A / m and 12.5 k A / m at 130 k H z ) to evaluate the thermal damage (Arrhenius ( Ω =4.6) and cumulative equivalent minutes C E M 43 60 in the tissue. Results show that there exists a critical depth, which is nearly half of the tumor size, up to which the MNH is influenced by the position of the tumor. Similarly, the effects of the ambient conditions during this thermotherapy on thermal dosimetry, also cease beyond this critical depth. The estimation of the critical depth of the tumor will help in predicting the therapeutic effects of magnetic hyperthermia applicators for specifically positioned tumors in actual environmental conditions.

Therapeutic targeting of PD-1/PD-L1 blockade by novel small-molecule inhibitors recruits cytotoxic T cells into solid tumor microenvironment

BackgroundInhibiting programmed cell death protein 1 (PD-1) or PD-ligand 1 (PD-L1) has shown exciting clinical outcomes in diverse human cancers. So far, only monoclonal antibodies are approved as PD-1/PD-L1 inhibitors....