Bimodality imaging as a companion to evaluate antitumour efficacy of TH-302 in experimental chondrosarcoma

Tumor microenvironment in cancer treatment and metastasis

Background: Increasing evidence showed that the clinical significance of the interaction between hypoxia and immune status in tumor microenvironment. However, reliable biomarkers based on the hypoxia and immune status in triple-negative breast cancer (TNBC) have not been well established. This study aimed to explore a gene signature based on the hypoxia and immune status for predicting prognosis, risk stratification, and individual treatment in TNBC.Methods: Hypoxia-related genes (HRGs) and Immune-related genes (IRGs) were identified using the weighted gene co-expression network analysis (WGCNA) method and the single-sample gene set enrichment analysis (ssGSEA Z-score) with the transcriptomic profiles from Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) cohort. Then, prognostic hypoxia and immune based genes were identified in TNBC patients from the METABRIC (N = 221), The Cancer Genome Atlas (TCGA) (N = 142), and GSE58812 (N = 107) using univariate cox regression model. A robust hypoxia-immune based gene signature for prognosis was constructed using the least absolute shrinkage and selection operator (LASSO) method. Based on the cross-cohort prognostic hypoxia–immune related gene signature, a comprehensive index of hypoxia and immune was developed and two risk groups with distinct hypoxia–immune status were identified. The prognosis value, hypoxia and immune status, and therapeutic response in different risk groups were analyzed. Furthermore, a nomogram was constructed to predict the prognosis for individual patients, and an independent cohort from the gene expression omnibus (GEO) database was used for external validation.Results: Six cross-cohort prognostic hypoxia–immune related genes were identified to establish the comprehensive index of hypoxia and immune. Then, patients were clustered into high- and low-risk groups based on the hypoxia–immune status. Patients in the high-risk group showed poorer prognoses to their low-risk counterparts, and the nomogram we constructed yielded favorable performance to predict survival and risk stratification. Besides, the high-risk group had a higher expression of hypoxia-related genes and correlated with hypoxia status in tumor microenvironment. The high-risk group had lower fractions of activated immune cells, and exhibited lower expression of immune checkpoint markers. Furthermore, the ratio of complete response (CR) was greatly declined, and the ratio of breast cancer related events were significantly elevated in the high-risk group.Conclusion: The hypoxia–immune based gene signature we constructed for predicting prognosis was developed and validated, which may contribute to the optimization of risk stratification for prognosis and personalized treatment in TNBC patients.

Immunotherapy is an emerging building block of modern oncology, after chimeric antigen receptor (CAR) T cells demonstrated groundbreaking survival rates in hematological malignancies. However, therapy success in more common solid tumors has not been achieved yet, due to a variety of obstacles, such as a limited availability of suitable targets and decreased CAR T cells trafficking to the tumor. One of these barriers is the tumor microenvironment (TME), which is most pronounced in pancreatic ductal adenocarcinoma (PDAC). Combinatorial 2D and 3D preclinical multimodal imaging and cell tracking strategies can help to understand the mechanism that play a role in the solid tumor-specific barriers for CAR T cell migration. To this end, three non-solid CARs were characterized in vitro for killing and cytokine expression as well as for in vivo efficacy and tumor control. While in vitro results showed a potent killing and cytokine profile for all three CARs, in vivo analysis revealed a diminished killing potential of one CAR carrying an unspecifically bound IgG1-based spacer. This demonstrates the importance of imaging techniques to identify the most promising CARs for clinical transfer, to depict problematic CAR components and to unravel the underlying mechanisms. Furthermore, in vivo imaging identified the relevance of the CAR spacer domain, which is normally neglected. Favorable targeting of membrane-proximal epitopes with spacer, structural comparable to IgG1, encouraged the development of a novel spacer class, derived from sialic acid-binding immunoglobulin-type lectin (Siglec). Next, CAR T cells, incorporating the new spacers, were evaluated in vitro and ex vivo in solid and hematological malignancies. The functionality of the novel Siglec-4 derived spacer was superior to the established IgG4 and CD8α spacers in terms of the cytotoxic potential and a more potent anti-tumor marker and cytokine expression profile in comparison to IgG1-based spacers, supportive for future clinical trials. These results displayed the general functionality of CAR T cells against PDAC under the optimal conditions, in terms of target specificity, CAR composition and cell number and emphasize the implication of advanced imaging strategies for preclinical CAR T cell research. Thus, a rational multimodal imaging workflow was established and evaluated in a xenograft PDAC mouse model. First, optical 3D in vivo tracking of modified luciferase-expressing CAR T cells was applied. 3D Bioluminescence tomography (BLT) enabled the analysis of whole-body CAR T cells biodistribution and detection of pronounced CAR T cell accumulation in tumor and spleen in PDAC bearing mice. Subsequent combination with ex vivo light-sheet fluorescence microscopy (LSFM) of xenografts facilitated the generation of data visualizing whole-body and intratumoral T cell distribution of two different CARs. The addition of cyclic immunofluorescence staining (IF) provided an in-depth characterization of tumor-infiltrating CAR T cells and surrounding tumor cells, revealing strong activation and proliferation of target-specific CAR T cells. The multi-modal imaging strategy enabled the evaluation of locally applied interleukin-2 (IL-2) as a support for CAR T cells in the immunosuppressive TME of PDAC. IL-2, repeatedly injected at the tumor site was shown to negatively impact intratumoral T cell distribution and phenotype. IL-2 co-treated CAR T cells infiltrated the tumor tissue less deep and showed a more overstimulated phenotype. These cells were no longer able to perform sufficient tumor eradication and local IL-2 did not translate into an enhanced anti-tumor efficacy. Taken together, this project established optical 3D CAR T cell tracking as part of a combined in vivo and ex vivo workflow for solid tumor cell therapy, TME-redirected treatment protocols and safety-orientated research. This preclinical imaging strategy enables the in-depth characterization of combinatorial CAR T cell approaches against solid tumors and TME in a mouse model of PDAC.

Background:Photodynamic therapy (PDT) is a treatment modality for a range of diseases including cancer. The BF2-chelated tetraaryl-azadipyrromethenes (ADPMs) are an emerging class of non-porphyrin PDT agent, which have previously shown excellent photochemical and photophysical properties for therapeutic application. Herein, in vivo efficacy and mechanism of action studies have been completed for the lead agent, ADMP06.Methods:A multi-modality imaging approach was employed to assess efficacy of treatment, as well as probe the mechanism of action of ADPM06-mediated PDT.Results:Tumour ablation in 71% of animals bearing mammary tumours was achieved after delivery of 2 mg kg−1 of ADPM06 followed immediately by light irradiation with 150 J cm−2. The inherent fluorescence of ADPM06 was utilised to monitor organ biodistribution patterns, with fluorescence reaching baseline levels in all organs within 24 h. Mechanism of action studies were carried out using dynamic positron emission tomography and magnetic resonance imaging techniques, which, when taken together, indicated a decrease in tumour vascular perfusion and concomitant reduction in tumour metabolism over time after treatment.Conclusion:The encouraging treatment responses in vivo and vascular-targeting mechanism of action continue to indicate therapeutic benefit for this new class of photosensitiser.

Although metabolic modulation in the tumor microenvironment (TME) is one of the key mechanisms of cancer immune escape, there is a lack of understanding of the comprehensive immune landscape of the TME and its association with tumor metabolism based on clinical evidence. We aimed to investigate the relationship between the immune landscape in the TME and tumor glucose metabolism in lung adenocarcinoma.Methods: Using RNA sequencing and image data, we developed a transcriptome-based tumor metabolism estimation model. The comprehensive TME cell types enrichment scores and overall immune cell enrichment (ImmuneScore) were estimated. Subjects were clustered by cellular heterogeneity in the TME and the clusters were characterized by tumor glucose metabolism and immune cell composition. Moreover, the prognostic value of ImmuneScore, tumor metabolism and the cell type-based clusters was also evaluated.Results: Four clusters were identified based on the cellular heterogeneity in the TME. They showed distinct immune cell composition, different tumor metabolism, and close relationship with overall survival. A cluster with high regulatory T cells showed relative hypermetabolism and poor prognosis. Another cluster with high mast cells and CD4+ central memory T cells showed relative hypometabolism and favorable prognosis. A cluster with high ImmuneScore showed favorable prognosis. Multivariate Cox analysis demonstrated that ImmuneScore was a predictive prognostic factor independent of other clinical features.Conclusions: Our results showed the association between predicted tumor metabolism and immune cell composition in the TME. Our studies also suggest that tumor glucose metabolism and immune cell infiltration in the TME can be clinically applicable for developing a prognostic stratification model.

By combining the strengths of various imaging modalities, the multimodality imaging approach has potential to improve tumor staging, delineation of tumor boundaries, chemo-radiotherapy regime design, and treatment response assessment in cancer management. To address the urgent needs for efficient tools to analyze large-scale clinical trial data, we have developed an integrated multimodality, functional and anatomical imaging analysis software package for target definition and therapy response assessment in pediatric radiotherapy (RT) patients. Our software provides quantitative tools for automated image segmentation, region-of-interest (ROI) histogram analysis, spatial volume-of-interest (VOI) analysis, and voxel-wise correlation across modalities. To demonstrate the clinical applicability of this software, histogram analyses were performed on baseline and follow-up ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) PET images of nine patients with rhabdomyosarcoma enrolled in an institutional clinical trial at St. Jude Children's Research Hospital. In addition, we combined ¹⁸F-FDG PET, dynamic-contrast-enhanced (DCE) MR, and anatomical MR data to visualize the heterogeneity in tumor pathophysiology with the ultimate goal of adaptive targeting of regions with high tumor burden. Our software is able to simultaneously analyze multimodality images across multiple time points, which could greatly speed up the analysis of large-scale clinical trial data and validation of potential imaging biomarkers.

The expression and activity of lactate dehydrogenase A (LDH-A) in malignant tissue is considered a prognostic marker of poor outcome in many tumors. A limitation of tissue LDH-A measurements is the requirement of tissue for assay. The development of new non-invasive methods is highly demanded for clinical evaluation. One mechanistic link between tumor cell metabolism and the activity of lactate dehydrogenase A (LDH-A) is based on the HIF-1 transcription factor and its upregulation in tumors. HIF-1 binds to the LDH-A promoter and increases LDH-A expression; this in turn results in increased lactic acid production. The objective of this study was to detect the metabolic changes during tumor growth using a multi-modality imaging approach. To monitor HIF-1 pathway activity by bioluminescence imaging (BLI), we cloned an external Gaussia luciferase (exGLuc) reporter gene into an -IRES-GFP cassette, and placed the cassette in a self-inactivated retroviral vector under the control of an enhancer, containing multiple copies of the binding sites for the HIF-1 transcription factor. 18F-fluorodeoxyglucose (FDG)/microPET imaging was used for the detection of glucose metabolism in tumors, while lactate production was measured by proton magnetic resonance spectroscopic imaging (MRI/S). To validate this multi-modality imaging approach, human glioblastoma U87MG cells were transduced with the HIF-1 reporter vector and the HIF-1 reporter response was validated in vitro by exposure cells to hypoxia (1% O2) and to CoCl2 or DFO (deferoxamine mesylate). Despite a high basal level of HIF-1 transcriptional activity in the U87MG reporter cells, a strong correlation between oxygen deprivation and the level of exGLuc/GFP expression (indicating HIF-1 transcriptional activation) was detected, and this increase corresponded with a significant increase in LDH-A expression, assessed by immunoblotting. In vivo experiments using U87 reporter-xenografts also demonstrated a correspondence between the levels of HIF-1 expression and lactate production assessed by MRI/S. The measurement of lactate production using MRI/S with consecutive BLI imaging of HIF-1 activity and 18F fluorodeoxyglucose (FDG)/microPET confirmed the feasibility of a multi-modality imaging approach to study the link between the HIF-1 activity and a lactate production, as well as the level of glucose (FDG) uptake in growing xenografts. This multi-modal imaging paradigm can provide new and relevant information, and the opportunity to initiate and monitor more effective treatment strategies to arrest tumor growth. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5234.

The tumor microenvironment (TME) is made up of cells and extracellular matrix (non-cellular component), and cellular components include cancer cells and non-malignant cells such as immune cells and stromal cells. These three types of cells establish complex signals in the body and further influence tumor genesis, development, metastasis and participate in resistance to anti-tumor therapy. It has attracted scholars to study immune cells in TME due to the significant efficacy of immune checkpoint inhibitors (ICI) and chimeric antigen receptor T (CAR-T) in solid tumors and hematologic tumors. After more than 10 years of efforts, the role of immune cells in TME and the strategy of treating tumors based on immune cells have developed rapidly. Moreover, ICI have been recommended by guidelines as first- or second-line treatment strategies in a variety of tumors. At the same time, stromal cells is another major class of cellular components in TME, which also play a very important role in tumor metabolism, growth, metastasis, immune evasion and treatment resistance. Stromal cells can be recruited from neighboring non-cancerous host stromal cells and can also be formed by transdifferentiation from stromal cells to stromal cells or from tumor cells to stromal cells. Moreover, they participate in tumor genesis, development and drug resistance by secreting various factors and exosomes, participating in tumor angiogenesis and tumor metabolism, regulating the immune response in TME and extracellular matrix. However, with the deepening understanding of stromal cells, people found that stromal cells not only have the effect of promoting tumor but also can inhibit tumor in some cases. In this review, we will introduce the origin of stromal cells in TME as well as the role and specific mechanism of stromal cells in tumorigenesis and tumor development and strategies for treatment of tumors based on stromal cells. We will focus on tumor-associated fibroblasts (CAFs), mesenchymal stem cells (MSCs), tumor-associated adipocytes (CAAs), tumor endothelial cells (TECs) and pericytes (PCs) in stromal cells.

[Purpose] In pancreatic ductal adenocarcinoma (PDAC) which is characterized by an intense desmoplastic feature, the extracellular matrix (ECM) can significantly influence the tumor microenvironment (TME). Hyaluronan (HA), a major component of ECM, is associated with elevated tumor pressure, vascular collapse, and poor perfusion in TME, conferring hypoxia. HA expression is also correlated with poor prognosis in the patients with PDAC. PEGylated human hyaluronidase (PEGPH20) enzymatically depletes hyaluronan in tumors. The resultant improvement in vascular patency and blood perfusion is expected to increase the delivery of therapeutic molecules. The aim of this study was to investigate the change in physiologic and metabolic profile of the tumor in response to treatment with PEGPH20 using multi-modal imaging techniques. We also investigated the capability of PEGPH20 to enhance treatment effect of radiation. [Methods] Athymic nude mice were inoculated with BxPC3 (human pancreatic adenocarcinoma) tumor cells transduced with hyaluronan synthase 3 (HAS3) to the right tibial periosteum. BxPC3-HAS3 tumor treated with PEGPH20 or control buffer were scanned with Electron paramagnetic Resonance imaging (EPRI), dynamic contrast enhanced (DCE) MRI, ultra-small superparamagnetic iron oxide (USPIO) MRI, Photoacoustic imaging (PAI), and Hyperpolarized 13C-MRI using [1-13C] pyruvate to evaluate intratumor pO2, intratumor perfusion, blood volume, O2 saturation, and glycolysis, respectively. [Results] EPRI showed significantly increased pO2 in PEGPH20 treated group. DCE-MRI and USPIO-MRI showed improved perfusion/permeability and local blood volume, respectively after PEGPH20 treatment, accounting for the increase in tumor oxygenation. PAI provided the evidence of immediate changes in tumor oxygenation after treatment. Hyperpolarized 13C-MRI using [1-13C] pyruvate suggested the decreased glycolytic flux evaluated by lactate/pyruvate ratio after PEGPH20 treatment. Combination of radiotherapy and PEGPH20 synergistically delayed tumor progression and prolonged the survival. [Conclusions] This study examined the effect of PEGPH20 on TME in PDAC xenograft model by using non-invasive multimodal imaging techniques. In summary, the non-invasive imaging modalities were useful in evaluating the changes in hemodynamics and metabolism in TME induced by modulation of ECM such as PEGPH20 treatment. PEGPH20 enhanced treatment effect of radiation therapy. The results validated the utility of the imaging methods to non-invasively monitor the changes in TME and predicted the radiosensitizing effect of hyaluronan depletion. Citation Format: Yu Saida, Tomohiro Seki, Shun Kishimoto, Jeffrey R. Brender, Gadisetti VR. Chandramouli, Yasunori Otowa, Kota Yamashita, Kazutoshi Yamamoto, Nallathamby Devasahayam, Murali C. Krishna. Multimodal molecular imaging detects early reoxygenation induced by hyaluronan depletion in pancreatic cancer model mouse [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5974.

Noninvasive “multimodal” in vivo imaging is not just becoming standard practice in the clinic, but is rapidly changing the evolving field of experimental imaging of genetic expression (“molecular imaging”). The development of multimodality methodology based on nuclear medicine (NM), positron emission tomography (PET) imaging, magnetic resonance imaging (MRI), and optical imaging is the single biggest focus in many imaging and cancer centers worldwide and is bringing together researchers and engineers from the far-ranging fields of molecular pharmacology to nanotechnology engineering. The rapid growth of in vivo multimodality imaging arises from the convergence of established fields of in vivo imaging technologies with molecular and cell biology. The cross-pollination of these disciplines has been accelerated in part by the establishment of the National Institutes of Health NCI P20 and P50 awards, for example, and by the sheer potential of the technology. Multimodality imaging is widely considered to involve the incorporation of two or more imaging modalities, usually within the setting of a single examination using, for example, dual- or triple-labeled optical or nuclear medicine “reporter” agents or by performing ultrasound or optical studies within the MR, single-photon emission computed tomography (SPECT), or x-ray computed tomography (CT) environment. Clinically, the best example of multimodality imaging is seen in the rapid evolution of PET-SPECT and PET-CT scanner hybrids. The PET modality has developed into perhaps the most used “multimodal” imaging method. The incorporation of PET into single, hybrid, and multimodality units to provide functional (typically from injected F-18DG studies) and anatomic information is becoming extremely popular,1–2 so much so that, for example, PET/CT hybrids can be found in outpatient screening centers located in shopping malls. The role of any multimodal imaging …

Multi-modality and multi-parametric molecular and functional imaging provide windows into the tumor microenvironment (TME) and into the interactions between cancer cells and stromal cells. Tumors have abnormal physiological environments such as hypoxia and acidic extracellular pH that influence the cancer cell-stromal cell interaction, generate a more aggressive phenotype, and play a major role in the response to treatment. The influence of hypoxia and acidic extracellular pH on the cancer cell phenotype has justifiably received significant attention. Magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS) and MR spectroscopic imaging (MRSI) techniques have been used for several decades to characterize physiologic parameters such as tumor vasculature, oxygenation, and necrosis, pH and metabolism. The bench to bedside span of noninvasive MR methods to characterize cancer makes them an attractive choice for clinically translatable applications. Recent advances in the development of molecular targeted contrast agents have expanded the traditional strengths of MRI and MRS of characterizing functional tumor parameters such as pH, vascularization, metabolism and cell death, to include visualization of stromal cells, cell surface receptors, molecular pathways, degradative enzyme activity, and the extracellular matrix integrity in preclinical models. The TME is rich with targets to exploit for therapy that can be used in combination with imaging for ‘theranostic’ imaging agents. The use of MR biomarkers such as total choline and perfusion are already being explored clinically for characterizing tumors and following treatment response. The elevation of choline compounds presents a unique target to exploit for molecular targeting; such targeting can be imaged noninvasively with MRS. We are developing molecular and molecular imaging based approaches to target choline metabolism, specifically choline kinase activity, which is the first step in choline phospholipid biosynthesis. New areas that are being developed in our program include targeting choline kinase using siRNA delivered using lentiviral vectors, and performing image-guided targeting of choline kinase using siRNA in combination with a prodrug enzyme cytosine deaminase using a multi-modal imaging platform. The interaction between cancer cells and the tumor microenvironment is providing new insights into the etiology and progression of cancer. Using combined MR and optical imaging of human breast and prostate cancer xenografts engineered to express green fluorescent protein (GFP) or red fluorescent protein (RFP) under hypoxia, we have obtained useful insights into the dynamics between hypoxia and the tumor extracellular matrix (ECM), vascularization, extracellular pH, interstitial fluid transport, and metabolism. MRI and MRSI were used to obtain co-localized maps of vascular volume, permeability, interstitial fluid transport, total choline and lactate/lipid, while optical imaging was used to obtain co-localized maps of hypoxia and ECM fiber distribution. These insights can be exploited to find effective treatment strategies. Tumor recurrence and metastasis continue to be the leading causes of morbidity and mortality from cancer and, despite the tremendous advances in cancer research and treatment, even in the twenty-first century cancer continues to evade cure and frequently control. The discovery of cancer initiating cells or cancer stem cells is generating tremendous excitement and is offering new paradigms for understanding and treating cancer recurrence and metastasis. These stem-like cancer cell populations can form tumors in immune suppressed mice from low cell number inoculums, are more drug resistant, more invasive, and more likely to metastasize. Identifying biomarkers associated with cancer stem cells, and imaging and targeting permissive or preventive microenvironmental niches for cancer stem cells is another area that will have significant impact on cancer research and treatment. A major direction for the future will be to translate preclinical molecular imaging developments for use in the clinic. Exciting new areas that should rapidly develop in the future include targeting specific microenvironments or stromal compartments with theranostic agents. Unlike radiopharmaceuticals, the inherent insensitivity of MR methods will require that most molecular contrast agents be used at concentrations that will be subject to much more stringent FDA control. Challenges for the future will be to increase the sensitivity of detection of such agents through novel chemistry, or instrumentation and the incorporation of multi-modality imaging. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY42-01. doi:1538-7445.AM2012-SY42-01

Neutrophil extracellular traps (NETs) are intricate, web-like formations composed of DNA, histones, and antimicrobial proteins, released by neutrophils. These structures participate in a wide array of physiological and pathological activities, including immune rheumatic diseases and damage to target organs. Recently, the connection between NETs and cancer has garnered significant attention. Within the tumor microenvironment and metabolism, NETs exhibit multifaceted roles, such as promoting the proliferation and migration of tumor cells, influencing redox balance, triggering angiogenesis, and driving metabolic reprogramming. This review offers a comprehensive analysis of the link between NETs and tumor metabolism, emphasizing areas that remain underexplored. These include the interaction of NETs with tumor mitochondria, their effect on redox states within tumors, their involvement in metabolic reprogramming, and their contribution to angiogenesis in tumors. Such insights lay a theoretical foundation for a deeper understanding of the role of NETs in cancer development. Moreover, the review also delves into potential therapeutic strategies that target NETs and suggests future research directions, offering new perspectives on the treatment of cancer and other related diseases.

Author response: Comprehensive characterization of tumor microenvironment in colorectal cancer via molecular analysis

Contrast agents (CAs) play a critical role in high-resolution magnetic resonance imaging (MRI) applications to enhance the low intrinsic sensitivity of MRI. Manganese oxide nanoparticles (MnO) have gotten developing consideration as substitute spinâ��lattice (T1) MRI CAs as a result of the Gd-based CAs which are related with renal i¬�brosis as well as the inherent dark imaging characteristics of superparamagnetic iron oxide NPs. In this review, previous developments in the usage of MnO nanoparticles as MRI CAs for cancer theranostic applications such as developments in toxicological properties, distribution and tumor microenvironment (TME)-responsive biomaterials were reviewed. A literature search was accomplished to discover distributed research that elaborates the use of MnO in multimodal imaging and therapy. In the current study, the electronic search including PubMed/Medline, Embase, ProQuest, Scopus, Cochrane and Google Scholar was performed dependent on Mesh key words. CAs can significantly improve the imaging contrast among the lesions and normal tissues. In this study we generally concentrate on typical advancements of MnO nanoparticles about properties, bimodal or multimodal imaging, and therapy. Numerous researches have demonstrated MnO-based nanostructure produce considerable biocompatibility with the lack of cytotoxicity. Therefore, remarkable features improved photothermal therapy, chemotherapy and Chemodynamic therapy.

Engineering the Extracellular Matrix to Model the Evolving Tumor Microenvironment.