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Tumor development and metastasis are facilitated by the complex interactions between cancer cells and their microenvironment, which comprises stromal cells and extracellular matrix (ECM) components, among other factors. Stromal cells can adopt new phenotypes to promote tumor cell invasion. A deep understanding of the signaling pathways involved in cell‐to‐cell and cell‐to‐ECM interactions is needed to design effective intervention strategies that might interrupt these interactions. In this review, we describe the tumor microenvironment (TME) components and associated therapeutics. We discuss the clinical advances in the prevalent and newly discovered signaling pathways in the TME, the immune checkpoints and immunosuppressive chemokines, and currently used inhibitors targeting these pathways. These include both intrinsic and non‐autonomous tumor cell signaling pathways in the TME: protein kinase C (PKC) signaling, Notch, and transforming growth factor (TGF‐β) signaling, Endoplasmic Reticulum (ER) stress response, lactate signaling, Metabolic reprogramming, cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) and Siglec signaling pathways. We also discuss the recent advances in Programmed Cell Death Protein 1 (PD‐1), Cytotoxic T‐Lymphocyte Associated Protein 4 (CTLA4), T‐cell immunoglobulin mucin‐3 (TIM‐3) and Lymphocyte Activating Gene 3 (LAG3) immune checkpoint inhibitors along with the C‐C chemokine receptor 4 (CCR4)‐ C‐C class chemokines 22 (CCL22)/ and 17 (CCL17), C‐C chemokine receptor type 2 (CCR2)‐ chemokine (C‐C motif) ligand 2 (CCL2), C‐C chemokine receptor type 5 (CCR5)‐ chemokine (C‐C motif) ligand 3 (CCL3) chemokine signaling axis in the TME. In addition, this review provides a holistic understanding of the TME as we discuss the three‐dimensional and microfluidic models of the TME, which are believed to recapitulate the original characteristics of the patient tumor and hence may be used as a platform to study new mechanisms and screen for various anti‐cancer therapies. We further discuss the systemic influences of gut microbiota in TME reprogramming and treatment response. Overall, this review provides a comprehensive analysis of the diverse and most critical signaling pathways in the TME, highlighting the associated newest and critical preclinical and clinical studies along with their underlying biology. We highlight the importance of the most recent technologies of microfluidics and lab‐on‐chip models for TME research and also present an overview of extrinsic factors, such as the inhabitant human microbiome, which have the potential to modulate TME biology and drug responses.

Chimeric antigen receptor (CAR)-T cell therapy is a progressive new pillar in immune cell therapy for cancer. It has yielded remarkable clinical responses in patients with B-cell leukemia or lymphoma. Unfortunately, many challenges remain to be addressed to overcome its ineffectiveness in the treatment of other hematological and solidtumor malignancies. The major hurdles of CAR T-cell therapy are the associated severe life-threatening toxicities such as cytokine release syndrome and limited anti-tumor efficacy. In this review, we briefly discuss cancer immunotherapy and the genetic engineering of T cells and, In detail, the current innovations in CAR T-cell strategies to improve efficacy in treating solid tumors and hematologic malignancies. Furthermore, we also discuss the current challenges in CAR T-cell therapy and new CAR T-cell-derived nanovesicle therapy. Finally, strategies to overcome the current clinical challenges associated with CAR T-cell therapy are included as well.

Extracellular vesicles (EVs) are small membrane-based nanovesicles naturally released from cells. Extracellular vesicles mimetics (EVMs) are artificial vesicles engineered from cells or in combination with lipid materials, and they mimic certain characteristics of EVs. As such, EVs facilitate intracellular communication by carrying and delivering biological materials, such as proteins, lipids, and nucleic acids, and they have been found to find organ tropism in preclinical studies. Because of their native structure and characteristics, they are considered promising drug carriers for future clinical use. This review outlines the origin and composition of natural EVs and EVM engineering and internalization. It then details different loading approaches, with examples of the drug delivery of therapeutic molecules. In addition, the advantages and disadvantages of loading drugs into EVs or EVMs as a drug delivery system are discussed. Finally, the advantages of EVMs over EVs and the future clinical translation of EVM-based drug delivery platforms are outlined.

Extracellular vesicles (EVs) are currently being considered as promising drug delivery vehicles. EVs are naturally occurring vesicles that exhibit many characteristics favorable to serve as drug delivery vehicles. In addition, EVs have inherent properties for treatment of cancers and other diseases. For research and clinical translation of use of EVs as drug delivery vehicles, tracking of EVs is essential. The latest molecular imaging techniques enable the tracking of EVs in living animals. However, each molecular imaging technique has its certain advantages and limitations for the imaging of EVs; therefore, understanding the molecular imaging techniques is essential to select the most appropriate imaging technology to achieve the desired imaging goal. In this review, we summarize the characteristics of EVs as drug delivery vehicles and the molecular imaging techniques used in visualizing and monitoring EVs in environments. Furthermore, we provide a perceptual vision of EVs as drug delivery vehicles and monitoring of EVs using molecular imaging technologies.

Molecular imaging based personalized therapy has been a fascinating concept for individualized therapeutic strategy, which is able to attain the highest efficacy and reduce adverse effects in certain patients. Theranostics, which integrates diagnostic testing to detect molecular targets for particular therapeutic modalities, is one of the key technologies that contribute to the success of personalized medicine. Although the term “theranostics” was used after the second millennium, its basic principle was applied more than 70 years ago in the field of thyroidology with radioiodine molecular imaging. Differentiated thyroid cancer, which arises from follicular cells in the thyroid, is the most common endocrine malignancy, and theranostic radioiodine has been successfully applied to diagnose and treat differentiated thyroid cancer, the applications of which were included in the guidelines published by various thyroid or nuclear medicine societies. Through better pathophysiologic understanding of thyroid cancer and advancements in nuclear technologies, theranostic radioiodine contributes more to modern tailored personalized management by providing high therapeutic effect and by avoiding significant adverse effects in differentiated thyroid cancer. This review details the inception of theranostic radioiodine and recent radioiodine applications for differentiated thyroid cancer management as a prototype of personalized medicine based on molecular imaging.

Macrophages are important precursor cell types of the innate immune system and bridge adaptive immune responses through the antigen presentation system. Meanwhile, macrophages constitute substantial portion of the stromal cells in the tumor microenvironment (TME) (referred to as tumor-associated macrophages, or TAMs) and exhibit conflicting roles in the development, invasion, and metastasis of thyroid cancer (TC). Moreover, TAMs play a crucial role to the behavior of TC due to their high degree of infiltration and prognostic relevance. Generally, TAMs can be divided into two subgroups; M1-like TAMs are capable of directly kill tumor cells, and recruiting and activating other immune cells in the early stages of cancer. However, due to changes in the TME, M2-like TAMs gradually increase and promote tumor progression. This review aims to discuss the impact of TAMs on TC, including their role in tumor promotion, gene mutation, and other factors related to the polarization of TAMs. Finally, we will explore the M2-like TAM-centered therapeutic strategies, including chemotherapy, clinical trials, and combinatorial immunotherapy.

Hepatotoxicity is a major global public health concern. Despite advances in modern medicine, the demerits of chemically prepared drugs outweigh their merits. In addition, the treatment of liver diseases based on modern medical principles has been found to produce several undesired side effects. Therefore, the exploration of medicinal plants has gained worldwide attention for treating various diseases, including liver diseases, owing to their potential efficacy and cost effectiveness. Several plants, including Andrographis paniculata, Bauhinia purpurea, Commelina nudiflora, Dillenia suffruticosa, Elaeis guineensis, Lygodium microphyllum, and Nephrolepis biserrata, have been reported with hepatoprotection. Moreover, these plants have been shown to play a vital role in ameliorating cellular damage because they contain several phytochemicals, including alkaloids, saponins, flavonoids, tannins, terpenoids, steroids, polyphenols, and diterpenoid lactones. The following antioxidant, anti-inflammatory, immunomodulatory, and hepatoprotective compounds have been found in these plants: andrographolide, rosmarinic acid, phenol, eugenol, 9,12-octadecadienoic, n-hexadecanoic acid, dihydroxy dimethoxy flavone, sitosterol, demethoxycurcumin, quercetin, linoleic acid, stigmasterol, kojic acid, indole-2-one, α-terpinol, linalool, kaempferol, catechin, ellagic acid, and oleanolic acid. This paper aimed to provide an in-depth review of in vivo studies on Malaysian medicinal plants possessing hepatoprotective properties, phytochemical ingredients, and antioxidant mechanisms, with an emphasis on the species proven particularly useful for treating hepatic disorders.

Chalcones are a class of privileged scaffolds with high medicinal significance due to the presence of an α,β-unsaturated ketone functionality. Numerous functional modifications of chalcones have been reported, along with their pharmacological behavior. The present review aims to summarize the structures from natural sources, synthesis methods, biological characteristics against infectious and non-infectious diseases, and uses of chalcones over the past decade, and their structure–activity relationship studies are detailed in depth. This critical review provides guidelines for the future design and synthesis of various chalcones. In addition, this could be highly supportive for medicinal chemists to develop more promising candidates for various infectious and non-infectious diseases.

BACKGROUNDMolecular characterization in pediatric papillary thyroid cancer (PTC), distinct from adult PTC, is important for developing molecularly targeted therapies for progressive radioiodine-refractory (131I-refractory) PTC.METHODSPTC samples from 106 pediatric patients (age range: 4.3-19.8 years; n = 84 girls, n = 22 boys) who were admitted to SNUH (January 1983-March 2020) were available for genomic profiling. Previous transcriptomic data from 125 adult PTC samples were used for comparison.RESULTSWe identified genetic drivers in 80 tumors: 31 with fusion oncogenes (RET in 21 patients, ALK in 6 patients, and NTRK1/3 in 4 patients); 47 with point mutations (BRAFV600E in 41 patients, TERTC228T in 2 patients [1 of whom had a coexisting BRAFV600E], and DICER1 variants in 5 patients); and 2 with amplifications. Fusion oncogene PTCs, which are predominantly detected in younger patients, were at a more advanced stage and showed more recurrent or persistent disease compared with BRAFV600E PTCs, which are detected mostly in adolescents. Pediatric fusion PTCs (in patients <10 years of age) had lower expression of thyroid differentiation genes, including SLC5A5, than did adult fusion PTCs. Two girls with progressive 131I-refractory lung metastases harboring a TPR-NTRK1 or CCDC6-RET fusion oncogene received fusion-targeted therapy; larotrectinib and selpercatinib decreased the size of the tumor and restored 125I radioiodine uptake. The girl with the CCDC6-RET fusion oncogene received 131I therapy combined with selpercatinib, resulting in a tumor response. In vitro 125I uptake and 131I clonogenic assays showed that larotrectinib inhibited tumor growth and restored radioiodine avidity.CONCLUSIONSIn pediatric patients with fusion oncogene PTC who have 131I-refractory advanced disease, selective fusion-directed therapy may restore radioiodine avidity and lead to a dramatic tumor response, underscoring the importance of molecular testing in pediatric patients with PTC.FUNDINGThe Ministry of Science, ICT and Future Planning (NRF-2016R1A2B4012417 and 2019R1A2C2084332); the Korean Ministry of Health and Welfare (H14C1277); the Ministry of Education (2020R1A6A1A03047972); and the SNUH Research Fund (04-2015-0830).TRIAL REGISTRATIONTwo patients received fusion-targeted therapy with larotrectinib (NCT02576431; NAVIGATE) or selpercatinib (LOXO-RET-18018).

Exosomes, which are nano-sized transport bio-vehicles, play a pivotal role in maintaining homeostasis by exchanging genetic or metabolic information between different cells. Exosomes can also play a vital role in transferring virulent factors between the host and parasite, thereby regulating host gene expression and the immune interphase. The association of inflammation with disease development and the potential of exosomes to enhance or mitigate inflammatory pathways support the notion that exosomes have the potential to alter the course of a disease. Clinical trials exploring the role of exosomes in cancer, osteoporosis, and renal, neurological, and pulmonary disorders are currently underway. Notably, the information available on the signatory efficacy of exosomes in immune-related disorders remains elusive and sporadic. In this review, we discuss immune cell-derived exosomes and their application in immunotherapy, including those against autoimmune connective tissue diseases. Further, we have elucidated our views on the major issues in immune-related pathophysiological processes. Therefore, the information presented in this review highlights the role of exosomes as promising strategies and clinical tools for immune regulation.