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Simple Summary: Photodynamic therapy (PDT) is a cancer treatment that uses photogenerated reactive oxygen species (ROS) to damage target cells. The unique mechanism of action of PDT involves the systemic or local administration of a photosensitizing compound (photosensitizer), which is then activated by light of a specific energy. PDT induces a very strong local inflammatory response. A number of adaptive mechanisms are induced within the tumor, related to increased amino acid metabolism and damage to lymphatic vessels. In this review, we are describing the adaptive immune response induced by ROS and generated by PDT. Cancer is one of the most significant causes of death worldwide. Despite the rapid development of modern forms of therapy, results are still unsatisfactory. The prognosis is further worsened by the ability of cancer cells to metastasize. Thus, more effective forms of therapy, such as photodynamic therapy, are constantly being developed. The photodynamic therapeutic regimen involves administering a photosensitizer that selectively accumulates in tumor cells or is present in tumor vasculature prior to irradiation with light at a wavelength corresponding to the photosensitizer absorbance, leading to the generation of reactive oxygen species. Reactive oxygen species are responsible for the direct and indirect destruction of cancer cells. Photodynamically induced local inflammation has been shown to have the ability to activate an adaptive immune system response resulting in the destruction of tumor lesions and the creation of an immune memory. This paper focuses on presenting the latest scientific reports on the specific immune response activated by photodynamic therapy. We present newly discovered mechanisms for the induction of the adaptive response by analyzing its various stages, and the possible difficulties in generating it. We also present the results of research over the past 10 years that have focused on improving the immunological efficacy of photodynamic therapy for improved cancer therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Cuproptosis is a recently identified form of cell death induced by imbalanced copper levels. We aimed to explore the mechanism underlying copper-induced cell death. To achieve this, we surveyed the literature to understand the biochemical implications of cuproptosis in diseases, particularly in the context of cancer. The concept of copper ionophores, such as elesclomol and disulfiram, is highlighted as they elevate intracellular copper levels, triggering oxidative stress and ultimately leading to cell death–a potential avenue for cancer therapy. Furthermore, we will delve into the intricate relationship between copper, mitochondrial respiration, and protein lipoylation, shedding light on their connections in inducing cell death. Copper, an essential element for various biological processes, demands precise regulation to avert detrimental health effects and potential cell toxicity. This paper explores the mechanisms of copper-induced cell death, known as cuproptosis, and its potential health and disease implications, including cancer therapy. Copper ionophores, such as elesclomol and disulfiram, increase intracellular copper levels. This elevation triggers oxidative stress and subsequent cell death, offering potential implications in cancer therapy. Additionally, copper ionophores disrupt mitochondrial respiration and protein lipoylation, further contributing to copper toxicity and cell death. Potential targets and biomarkers are identified, as copper can be targeted to those proteins to trigger cuproptosis. The role of copper in different cancers is discussed to understand targeted cancer therapies using copper nanomaterials, copper ionophores, and copper chelators. Furthermore, the role of copper is explored through diseases such as Wilson and Menkes disease to understand the physiological mechanisms of copper. Exploring cuproptosis presents an opportunity to improve treatments for copper-related disorders and various cancers, with the potential to bring significant advancements to modern medicine. [ABSTRACT FROM AUTHOR]

Simple Summary: This paper provides a review of statistical methods for tumor-agnostic clinical trials. In particular, the review focuses on basket trials and provides methodological insights into various Bayesian approaches. The key concept of borrowing information through Bayesian hierarchical models is emphasized, and some novel trial designs are introduced. The review is expected to provide oncology and biostatistics researchers with more exposure to powerful Bayesian methods for the design and analysis of tumor-agnostic clinical trials. Basket trials allow simultaneous evaluation of a single therapy across multiple cancer types or subtypes of the same cancer. Since the same treatment is tested across all baskets, it may be desirable to borrow information across them to improve the statistical precision and power in estimating and detecting the treatment effects in different baskets. We review recent developments in Bayesian methods for the design and analysis of basket trials, focusing on the mechanism of information borrowing. We explain the common components of these methods, such as a prior model for the treatment effects that embodies an assumption of exchangeability. We also discuss the distinct features of these methods that lead to different degrees of borrowing. Through simulation studies, we demonstrate the impact of information borrowing on the operating characteristics of these methods and discuss its broader implications for drug development. Examples of basket trials are presented in both phase I and phase II settings. [ABSTRACT FROM AUTHOR]

Simple Summary: The expression of the cysteine–glutamate cotransporter, system xc−, is increased in cancer cells across many cancer types. Imaging system xc− provides new insights into tumour behaviour. The radiotracer (4S)-4-(3-[18F]Fluoropropyl)-L-glutamic acid (18F-FSPG) is specifically transported by system xc−, allowing for a non-invasive method of measuring this transporter's activity. This review summarises the data available on the use of 18F-FSPG in human cancer patients, exploring its advantages and disadvantages, and suggests possible future uses of 18F-FSPG in the assessment of early treatment response and treatment resistance. System xc− is upregulated in cancer cells and can be imaged using novel radiotracers, most commonly with (4S)-4-(3-[18F]fluoropropyl)-L-glutamic acid (18F-FSPG). The aim of this review was to summarise the use of 18F-FSPG in humans, explore the benefits and limitations of 18F-FSPG, and assess the potential for further use of 18F-FSPG in cancer patients. To date, ten papers have described the use of 18F-FSPG in human cancers. These studies involved small numbers of patients (range 1–26) and assessed the use of 18F-FSPG as a general oncological diagnostic agent across different cancer types. These clinical trials were contrasting in their findings, limiting the scope of 18F-FSPG PET/CT as a purely diagnostic agent, primarily due to heterogeneity of 18F-FSPG retention both between cancer types and patients. Despite these limitations, a potential further application for 18F-FSPG is in the assessment of early treatment response and prediction of treatment resistance. Animal models of cancer have shown that changes in 18F-FSPG retention following effective therapy precede glycolytic changes, as indicated by 18F-FDG, and changes in tumour volume, as measured by CT. If these results could be replicated in human clinical trials, imaging with 18F-FSPG PET/CT would offer an exciting route towards addressing the currently unmet clinical needs of treatment resistance prediction and early imaging assessment of therapy response. [ABSTRACT FROM AUTHOR]

Simple Summary: Neuroblastoma is a rare type of cancer that usually affects children. The high-risk patients' expected survival rate is less than 50%. One reason is the lack of precision in the standard treatment protocol: a one-size-fits-all multi-modal therapy. The study presented in this paper was designed to address this deficit by optimising the use of two chemotherapeutic agents—vincristine and cyclophosphamide—during induction chemotherapy—the part of the protocol that shrinks the primary tumour before surgical removal. We combined a mathematical model and an optimisation algorithm to identify the best chemotherapy schedules for a cohort of virtual patients with different initial tumour compositions. Our results reveal novel strategies to exploit a pair of drugs with different levels of efficacy, provide a platform on which to individualise induction chemotherapy, and lay the foundation for a personalised therapy that leverages targeted therapies, multi-region sequencing, liquid biopsies, and modern computational methods to improve today's multi-modal therapy. Neuroblastoma is the most common extra-cranial solid tumour in children. Despite multi-modal therapy, over half of the high-risk patients will succumb. One contributing factor is the one-size-fits-all nature of multi-modal therapy. For example, during the first step (induction chemotherapy), the standard regimen (rapid COJEC) administers fixed doses of chemotherapeutic agents in eight two-week cycles. Perhaps because of differences in resistance, this standard regimen results in highly heterogeneous outcomes in different tumours. In this study, we formulated a mathematical model comprising ordinary differential equations. The equations describe the clonal evolution within a neuroblastoma tumour being treated with vincristine and cyclophosphamide, which are used in the rapid COJEC regimen, including genetically conferred and phenotypic drug resistance. The equations also describe the agents' pharmacokinetics. We devised an optimisation algorithm to find the best chemotherapy schedules for tumours with different pre-treatment clonal compositions. The optimised chemotherapy schedules exploit the cytotoxic difference between the two drugs and intra-tumoural clonal competition to shrink the tumours as much as possible during induction chemotherapy and before surgical removal. They indicate that induction chemotherapy can be improved by finding and using personalised schedules. More broadly, we propose that the overall multi-modal therapy can be enhanced by employing targeted therapies against the mutations and oncogenic pathways enriched and activated by the chemotherapeutic agents. To translate the proposed personalised multi-modal therapy into clinical use, patient-specific model calibration and treatment optimisation are necessary. This entails a decision support system informed by emerging medical technologies such as multi-region sequencing and liquid biopsies. The results and tools presented in this paper could be the foundation of this decision support system. [ABSTRACT FROM AUTHOR]

Simple Summary: The Clonogenic Survival Assay (CSA) is pivotal in gauging cell survival and proliferative capacity in oncology research. However, it's limited by its binary output and its time- and labor-intensive nature. We developed LeGO-CSA, a refined version of CSA, utilizing imaging of cell nuclei tagged with fluorescent markers which encode red, green, blue fluorescent proteins and their variations. This facilitates both high-content and high-throughput analysis, delivering a potent tool for cancer research, promising heightened accuracy and efficiency, with the potential to expedite drug discovery and offer deeper insights into cellular dynamics in cancer. This transformative approach can revolutionize cancer research methodologies, making them more efficient and insightful. The Clonogenic Survival Assay (CSA) is a fundamental tool employed to assess cell survival and proliferative potential in cancer research. Despite its importance, CSA faces limitations, primarily its time- and labor-intensive nature and its binary output. To overcome these limitations and enhance CSA's utility, several approaches have been developed, focusing on increasing the throughput. However, achieving both high-content and high-throughput analyses simultaneously has remained a challenge. In this paper, we introduce LeGO-CSA, an extension of the classical CSA that employs the imaging of cell nuclei barcoded with fluorescent lentiviral gene ontology markers, enabling both high-content and high-throughput analysis. To validate our approach, we contrasted it with results from a classical assay and conducted a proof-of-concept screen of small-molecule inhibitors targeting various pathways relevant to cancer treatment. Notably, our results indicate that the classical CSA may underestimate clonogenicity and unveil intriguing aspects of clonal cell growth. We demonstrate the potential of LeGO-CSA to offer a robust approach for assessing cell survival and proliferation with enhanced precision and throughput, with promising implications for accelerating drug discovery and contributing to a more comprehensive understanding of cellular behavior in cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Natural killer cells are a part of the native immune response to cancer. NK cell-based immunotherapies are an emerging strategy to kill tumor cells. This paper reviews the role of NK cells, their mechanism of action for killing tumor cells, and the receptors which could serve as potential targets for signaling. In this review, the role of nanoparticles in NK cell activation and increased cytotoxicity of NK cells against cancer are highlighted. Natural killer (NK) cells are one of the first lines of defense against infections and malignancies. NK cell-based immunotherapies are emerging as an alternative to T cell-based immunotherapies. Preclinical and clinical studies of NK cell-based immunotherapies have given promising results in the past few decades for hematologic malignancies. Despite these achievements, NK cell-based immunotherapies have limitations, such as limited performance/low therapeutic efficiency in solid tumors, the short lifespan of NK cells, limited specificity of adoptive transfer and genetic modification, NK cell rejection by the patient's immune system, insignificant infiltration of NK cells into the tumor microenvironment (TME), and the expensive nature of the treatment. Nanotechnology could potentially assist with the activation, proliferation, near-real time imaging, and enhancement of NK cell cytotoxic activity by guiding their function, analyzing their performance in near-real time, and improving immunotherapeutic efficiency. This paper reviews the role of NK cells, their mechanism of action in killing tumor cells, and the receptors which could serve as potential targets for signaling. Specifically, we have reviewed five different areas of nanotechnology that could enhance immunotherapy efficiency: nanoparticle-assisted immunomodulation to enhance NK cell activity, nanoparticles enhancing homing of NK cells, nanoparticle delivery of RNAi to enhance NK cell activity, genetic modulation of NK cells based on nanoparticles, and nanoparticle activation of NKG2D, which is the master regulator of all NK cell responses. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer is basically a tough condition on a patient's body where cell grows uncontrollably. Normal cells are affected, which destroys the health of the patient. The main problem in cancer is spreading from one part to another. Therefore, the mathematical modeling of cancerous tumors integrates to check overall stability. A novel approach is introduced such as Bernstein polynomial with combination of genetic algorithm, sliding mode controller, and synergetic control. The proposed solution has easily eliminated cancerous cells within five days using synergetic control. In addition, five cases are incorporated to evaluate error function. In addition, a brief comparative study is added to contrast the simulation results with theoretical modeling. Cancerous tumor cells divide uncontrollably, which results in either tumor or harm to the immune system of the body. Due to the destructive effects of chemotherapy, optimal medications are needed. Therefore, possible treatment methods should be controlled to maintain the constant/continuous dose for affecting the spreading of cancerous tumor cells. Rapid growth of cells is classified into primary and secondary types. In giving a proper response, the immune system plays an important role. This is considered a natural process while fighting against tumors. In recent days, achieving a better method to treat tumors is the prime focus of researchers. Mathematical modeling of tumors uses combined immune, vaccine, and chemotherapies to check performance stability. In this research paper, mathematical modeling is utilized with reference to cancerous tumor growth, the immune system, and normal cells, which are directly affected by the process of chemotherapy. This paper presents novel techniques, which include Bernstein polynomial (BSP) with genetic algorithm (GA), sliding mode controller (SMC), and synergetic control (SC), for giving a possible solution to the cancerous tumor cells (CCs) model. Through GA, random population is generated to evaluate fitness. SMC is used for the continuous exponential dose of chemotherapy to reduce CCs in about forty-five days. In addition, error function consists of five cases that include normal cells (NCs), immune cells (ICs), CCs, and chemotherapy. Furthermore, the drug control process is explained in all the cases. In simulation results, utilizing SC has completely eliminated CCs in nearly five days. The proposed approach reduces CCs as early as possible. [ABSTRACT FROM AUTHOR]

Simple Summary: A novel human-sized alternating magnetic field (AMF) coil is researched, designed and evaluated using numerical methods to achieve magnetic nanoparticle hyperthermia therapy in deep-seated tumors while avoiding damage to normal tissues. This is achieved by utilizing a circular current's electric and magnetic field spatial distributions. The studies are done for pancreatic cancer. Computational electromagnetic and temperature distributions are presented for a full-body, 3D human model. The results showed that the proposed human-sized coil could provide clinically relevant AMF to cancerous regions while causing negligible Joule heating to normal tissue, compared to commonly used AMF coils. Magnetic nanoparticle (MNP) hyperthermia therapy is a treatment technique that can be used alone or as an adjunct to radiation and/or chemotherapies for killing cancer cells. During treatment, MNPs absorb a part of electromagnetic field (EMF) energy and generate localized heat when subjected to an alternating magnetic field (AMF). The MNP-absorbed EMF energy, which is characterized by a specific absorption rate (SAR), is directly proportional to AMF frequency and the magnitude of transmitting currents in the coil. Furthermore, the AMF penetrates inside tissue and induces eddy currents in electrically conducting tissues, which are proportional to the electric field (J = σE). The eddy currents produce Joule heating ( = 0.5·σ·E2) in the normal tissue, the rate of energy transfer to the charge carriers from the applied electric fields. This Joule heating contains only the electric field because the magnetic field is always perpendicular to the velocity of the conduction charges, i.e., it does not produce work on moving charge. Like the SAR due to MNP, the electric field produced by the AMF coil is directly proportional to AMF frequency and the magnitude of transmitting currents in the coil. As a result, the Joule heating is directly proportional to the square of the frequency and transmitter current magnitude. Due to the fast decay of magnetic fields from an AMF coil over distance, MNP hyperthermia treatment of deep-seated tumors requires high-magnitude transmitting currents in the coil for clinically achievable MNP distributions in the tumor. This inevitably produces significant Joule heating in the normal tissue and becomes more complicated for a standard MNP hyperthermia approach for deep-seated tumors, such as pancreatic, prostate, liver, lung, ovarian, kidney, and colorectal cancers. This paper presents a novel human-sized AMF coil and MNP hyperthermia system design for safely and effectively treating deep-seated cancers. The proposed design utilizes the spatial distribution of electric and magnetic fields of circular coils. Namely, it first minimizes the SAR due to eddy currents in the normal tissue by moving the conductors away from the tissue (i.e., increasing coils' radii), and second, it increases the magnetic field at the targeted area (z = 0) due to elevated coils (|z| > 0) by increasing the radius of the elevated coils (|z| > 0). This approach is a promising alternative aimed at overcoming the limitation of standard MNP hyperthermia for deep-seated cancers by taking advantage of the transmitter coil's electric and magnetic field distributions in the human body for maximizing AMF in tumor regions and avoiding damage to normal tissue. The human-sized coil's AMF, MNP activation, and eddy current distribution characteristics are investigated for safe and effective treatment of deep-seated tumors using numerical models. Namely, computational results such as AMF, Joule heating SAR, and temperature distributions are presented for a full-body, 3D human model. The SAR and temperature distributions clearly show that the proposed human-sized AMF coil can provide clinically relevant AMF to the region occupied by deep-seated cancers for the application of MNP hyperthermia therapy while causing less Joule heating in the normal tissues than commonly used AMF techniques. [ABSTRACT FROM AUTHOR]

Simple Summary: During COVID 19 pandemic, cancer patients, their caregivers and physicians needed to balance the challenges associated with pandemic ensuring cancer care. In this paper, we analysed ED visits during the 72 days of the pandemic in 2020 (Italian lockdown period) and compared them to the ED visits in the same calendar days in 2019 and 2021. We compared their severity, outcome (admission vs. discharge vs. death vs. hospice/palliative care), method of arrival to the ED and type of tumours affecting patients, suggesting that pandemic related emotional distress and hospital departmental reorganization could have nega-tively influenced ED admissions. Our aim was to highlight how much the government restrictive measures could have had an impact on emergency care for fragile patients such as cancer patients and help to understand how to reconcile the health needs of a specific class of patients with the need to protect public health. The coronavirus disease 2019 (COVID-19) pandemic has had a global impact. Patients with cancer, their caregivers, and physicians need to balance the challenges associated with COVID-19 while ensuring cancer care. Nevertheless, emotional distress and hospital departmental reorganization could have led to a decrease in ED admissions even among oncological patients. Methods: We compared the 72 days of the pandemic in 2020 with the same calendar days in 2019 and 2021, defining a 20% decrease in ED visits as clinically significant. We studied the cause for visit, its severity, outcome (admission vs. discharge vs. death vs. hospice/palliative care), the tumor site, and method of arrival to the ED for the 3 time periods. Results: A significant decrease in ED oncological visits was found in 2020 compared to 2019, before returning to similar numbers in 2021. Fear, anxiety, and worry, in addition to hospital departmental reorganization, surely had an important role in the delay of ED visits, which resulted in irreparable consequences. [ABSTRACT FROM AUTHOR]

Simple Summary: There is a large gap in knowledge amongst the oncology community of moderate hyperthermia use in cancer management. This review provides an overview of clinical data on the use of loco-regional and superficial hyperthermia in the adjunct management of cancers. It is updated using higher-level evidence from prospective, comparative studies and meta-analyses. The methodology and results are summarised and tabulated according to tumour type for easy reference. Regional hyperthermia therapy (RHT) is a treatment that applies moderate heat to tumours in an attempt to potentiate the effects of oncological treatments and improve responses. Although it has been used for many years, the mechanisms of action are not fully understood. Heterogenous practices, poor quality assurance, conflicting clinical evidence and lack of familiarity have hindered its use. Despite this, several centres recognise its potential and have adopted it in their standard treatment protocols. In recent times, significant technical improvements have been made and there is an increasing pool of evidence that could revolutionise its use. Our narrative review aims to summarise the recently published prospective trial evidence and present the clinical effects of RHT when added to standard cancer treatments. In total, 31 studies with higher-quality evidence across various subsites are discussed herein. Although not all of these studies are level 1 evidence, benefits of moderate RHT in improving local tumour control, survival outcomes and quality of life scores were observed across the different cancer subsites with minimal increase in toxicities. This paper may serve as a reference when considering this technique for specific indications. [ABSTRACT FROM AUTHOR]

Simple Summary: Interventional oncology provides minimally invasive alternatives to many traditional medical and surgical treatments, offering a potential cure, control, or palliative care for many types of cancer patients. The aim of this article is to comprehensively review new indications for locoregional interventional oncology treatments and summarize the expert discussion and report from the "MIOLive Meets SIO" (Society of Interventional Oncology) session during the last Mediterranean Interventional Oncology Live congress held in Rome, Italy. Interventional oncology (IO) employs image-guided techniques to perform minimally invasive procedures, providing lower-risk alternatives to many traditional medical and surgical therapies for cancer patients. Since its advent, due to rapidly evolving research development, its role has expanded to encompass the diagnosis and treatment of diseases across multiple body systems. In detail, interventional oncology is expanding its role across a wide spectrum of disease sites, offering a potential cure, control, or palliative care for many types of cancer patients. Due to its widespread use, a comprehensive review of the new indications for locoregional procedures is mandatory. This article summarizes the expert discussion and report from the "MIOLive Meet SIO" (Society of Interventional Oncology) session during the last MIOLive 2022 (Mediterranean Interventional Oncology Live) congress held in Rome, Italy, integrating evidence-reported literature and experience-based perceptions. The aim of this paper is to provide an updated review of the new techniques and devices available for innovative indications not only to residents and fellows but also to colleagues approaching locoregional treatments. [ABSTRACT FROM AUTHOR]

Simple Summary: The global burden of cancer is substantial and growing. Among 22 groups of diseases and injuries in the GBD 2019 study, cancer was second only to cardiovascular diseases for the number of deaths and years of life lost. There are no good therapeutic drugs to deal with tumors in clinical practice. This paper reviews the potential of phase separation as a new field of cancer research in addressing the unmet clinical needs of patients with cancer. Phase separation is now acknowledged as an essential biologic mechanism wherein distinct activated molecules assemble into a different phase from the surrounding constituents of a cell. Condensates formed by phase separation play an essential role in the life activities of various organisms under normal physiological conditions, including the advanced structure and regulation of chromatin, autophagic degradation of incorrectly folded or unneeded proteins, and regulation of the actin cytoskeleton. During malignant transformation, abnormally altered condensate assemblies are often associated with the abnormal activation of oncogenes or inactivation of tumor suppressors, resulting in the promotion of the carcinogenic process. Thus, understanding the role of phase separation in various biological evolutionary processes will provide new ideas for the development of drugs targeting specific condensates, which is expected to be an effective cancer therapy strategy. However, the relationship between phase separation and cancer has not been fully elucidated. In this review, we mainly summarize the main processes and characteristics of phase separation and the main methods for detecting phase separation. In addition, we summarize the cancer proteins and signaling pathways involved in phase separation and discuss their promising future applications in addressing the unmet clinical therapeutic needs of people with cancer. Finally, we explain the means of targeted phase separation and cancer treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: A significant proportion of people with cancer use forms of complementary medicine. Many factors contribute to cancer including some which are modifiable by the patient, such as stress, poor nutrition, vitamin D deficiency, poor sleep and lack of physical activity. This paper discusses why it is important that oncologists help cancer patients to address such factors, and why an integrative approach which combines evidence-based complementary medicines or therapies with orthodox treatment might lead to better outcomes for cancer patients. A significant proportion of cancer patients use forms of complementary medicine or therapies. An integrative approach to cancer management combines conventional medicine with evidence-based complementary medicines/therapies and lifestyle interventions, for the treatment and prevention of disease and the optimisation of health. Its basis is a holistic one; to treat the whole person, not just the disease. It makes use of adjunct technologies which may assist the clinician in diagnosis of early carcinogenesis and monitoring of treatment effectiveness. Many factors contribute to the development of cancer including some which are largely modifiable by the patient and which oncologists may be in a position to advise on, such as stress, poor nutrition, lack of physical activity, poor sleep, and Vitamin D deficiency. An integrative approach to addressing these factors may contribute to better overall health of the patient and better outcomes. Evidence-based complementary medicine approaches include the use of supplements, herbal medicine, various practices that reduce stress, and physical therapies. Individualised to the patient, these can also help address the symptoms and signs associated with cancer and its orthodox treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: In the past few years, clinical as well as regular scientists have been paying attention to medicinal applications of natural products. There are several investigations focusing on the potential beneficial effects of natural compounds in the treatment of different cancers. In the current comprehensive review paper, we first discuss three major mechanisms that control the effect of cancer therapy agents on tumor cells. This includes autophagy, apoptosis and the unfolded protein response. In the next step, we discuss how different natural compounds (more than 100 compounds) target cancer cells via the autophagy pathway and how this regulates stress response and cell death in cancer cells. Macroautophagy (autophagy) has been a highly conserved process throughout evolution and allows cells to degrade aggregated/misfolded proteins, dysfunctional or superfluous organelles and damaged macromolecules, in order to recycle them for biosynthetic and/or energetic purposes to preserve cellular homeostasis and health. Changes in autophagy are indeed correlated with several pathological disorders such as neurodegenerative and cardiovascular diseases, infections, cancer and inflammatory diseases. Conversely, autophagy controls both apoptosis and the unfolded protein response (UPR) in the cells. Therefore, any changes in the autophagy pathway will affect both the UPR and apoptosis. Recent evidence has shown that several natural products can modulate (induce or inhibit) the autophagy pathway. Natural products may target different regulatory components of the autophagy pathway, including specific kinases or phosphatases. In this review, we evaluated ~100 natural compounds and plant species and their impact on different types of cancers via the autophagy pathway. We also discuss the impact of these compounds on the UPR and apoptosis via the autophagy pathway. A multitude of preclinical findings have shown the function of botanicals in regulating cell autophagy and its potential impact on cancer therapy; however, the number of related clinical trials to date remains low. In this regard, further pre-clinical and clinical studies are warranted to better clarify the utility of natural compounds and their modulatory effects on autophagy, as fine-tuning of autophagy could be translated into therapeutic applications for several cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: Recent advances in the state of the art for early cancer detection and therapy have led to a paradigm shift in the way the disease is detected and treated. In particular, treatments have become much more targeted and localized to minimize systemic body-wide side effects common in traditional treatment methods such as chemotherapy. At the forefront of this revolution is the utilization of plasmonic gold nanoparticles, which have gained increasing attention as a highly effective nanoplatform ranging from drug delivery to plasmonics-enhanced treatments such as photothermal therapy. In this paper, we highlight several advances our laboratory has developed in the pursuit of cancer diagnostics and therapeutics by integrating plasmonics, photonics, and nanotechnology. We discuss the development and applications of plasmonics-active gold nanostar (GNS), a uniquely shaped nanoparticle with numerous branches that serve to greatly amplify the thermal generation at resonant wavelengths. GNS has also been successfully used in tumor imaging contexts from two-photon fluorescence to surface-enhanced Raman scattering (SERS) sensing and imaging. Finally, GNS has been coupled with immunotherapy applications to serve as an effective adjuvant to immune checkpoint inhibitors. This combination of GNS and immunotherapy, the so called synergistic immuno photo nanotherapy (SYMPHONY), has been shown to be effective at controlling long-lasting cancer immunity and metastatic tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: Recently, radiogenomics has played a significant role and offered a new understanding of cancer's biology and behavior in response to standard therapy. It also provides a more precise prognosis, investigation, and analysis of the patient's cancer. Over the years, Artificial Intelligence (AI) has provided a significant strength in radiogenomics. In this paper, we offer computational and oncological prospects of the role of AI in radiogenomics, as well as its offers, achievements, opportunities, and limitations in the current clinical practices. Radiogenomics, a combination of "Radiomics" and "Genomics," using Artificial Intelligence (AI) has recently emerged as the state-of-the-art science in precision medicine, especially in oncology care. Radiogenomics syndicates large-scale quantifiable data extracted from radiological medical images enveloped with personalized genomic phenotypes. It fabricates a prediction model through various AI methods to stratify the risk of patients, monitor therapeutic approaches, and assess clinical outcomes. It has recently shown tremendous achievements in prognosis, treatment planning, survival prediction, heterogeneity analysis, reoccurrence, and progression-free survival for human cancer study. Although AI has shown immense performance in oncology care in various clinical aspects, it has several challenges and limitations. The proposed review provides an overview of radiogenomics with the viewpoints on the role of AI in terms of its promises for computational as well as oncological aspects and offers achievements and opportunities in the era of precision medicine. The review also presents various recommendations to diminish these obstacles. [ABSTRACT FROM AUTHOR]

Simple Summary: Magnetic Resonance Imaging (MRI) is a consolidated imaging tool for the multiparametric assessment of tissues in various pathologies from degenerative and inflammatory diseases to cancer. In recent years, the continuous technological evolution of the equipment has led to the development of sequences that provide not only anatomical but also functional and metabolic information. In addition, there is a growing and emerging field of research in clinical applications using MRI to exploit the diagnostic and therapeutic capabilities of nanocompounds. This review illustrates the application of the most advanced magnetic resonance techniques in the field of nanomedicine. In the last decades, nanotechnology has been used in a wide range of biomedical applications, both diagnostic and therapeutic. In this scenario, imaging techniques represent a fundamental tool to obtain information about the properties of nanoconstructs and their interactions with the biological environment in preclinical and clinical settings. This paper reviews the state of the art of the application of magnetic resonance imaging in the field of nanomedicine, as well as the use of nanoparticles as diagnostic and therapeutic tools, especially in cancer, including the characteristics that hinder the use of nanoparticles in clinical practice. [ABSTRACT FROM AUTHOR]

Simple Summary: Mild hyperthermia is a technique that induces a local tumor temperature increase up to 43.0 °C. In this paper, we introduce three devices that could be used to apply hyperthermia in small animals in combination with intravital microscopy for the real-time visualization of in vivo intratumoral events such as drug delivery. This paper presents three devices suitable for the preclinical application of hyperthermia via the simultaneous high-resolution imaging of intratumoral events. (Pre)clinical studies have confirmed that the tumor micro-environment is sensitive to the application of local mild hyperthermia. Therefore, heating is a promising adjuvant to aid the efficacy of radiotherapy or chemotherapy. More so, the application of mild hyperthermia is a useful stimulus for triggered drug release from heat-sensitive nanocarriers. The response of thermosensitive nanoparticles to hyperthermia and ensuing intratumoral kinetics are considerably complex in both space and time. To obtain better insight into intratumoral processes, longitudinal imaging (preferable in high spatial and temporal resolution) is highly informative. Our devices are based on (i) an external electric heating adaptor for the dorsal skinfold model, (ii) targeted radiofrequency application, and (iii) a microwave antenna for heating of internal tumors. These models, while of some technical complexity, significantly add to the understanding of effects of mild hyperthermia warranting implementation in research on hyperthermia. [ABSTRACT FROM AUTHOR]

Simple Summary: (CAR)-T cell-based therapies have achieved substantial success against different haematological malignancies. However, results for solid tumours have been limited up to now, in part due to the fact that the immunosuppressive tumour microenvironment inactivates CAR-T cell clones. In this paper we study mathematically the competition of CAR-T and tumour cells, taking into account their immunosuppressive capacity. Using computer simulations, we show that the use of large numbers of CAR-T cells targetting the solid tumour antigens could overcome the immunosuppressive potential of cancer. To achieve such high levels of CAR-T cells we propose, and study in silico, the manufacture and injection of CAR-T cells targetting two antigens: CD19 and a tumour-associated antigen. This strategy lead in our simulations to the expansion of the CAR-T cells injected and the production of a massive army of CAR-T cells targetting the solid tumour, and potentially overcoming its immune suppression capabilities. Thus, our proposed strategy could provide a way to develop successful CAR-T cell therapies against solid tumours. Chimeric antigen receptor (CAR)-T cell-based therapies have achieved substantial success against B-cell malignancies, which has led to a growing scientific and clinical interest in extending their use to solid cancers. However, results for solid tumours have been limited up to now, in part due to the immunosuppressive tumour microenvironment, which is able to inactivate CAR-T cell clones. In this paper we put forward a mathematical model describing the competition of CAR-T and tumour cells, taking into account their immunosuppressive capacity. Using the mathematical model, we show that the use of large numbers of CAR-T cells targetting the solid tumour antigens could overcome the immunosuppressive potential of cancer. To achieve such high levels of CAR-T cells we propose, and study computationally, the manufacture and injection of CAR-T cells targetting two antigens: CD19 and a tumour-associated antigen. We study in silico the resulting dynamics of the disease after the injection of this product and find that the expansion of the CAR-T cell population in the blood and lymphopoietic organs could lead to the massive production of an army of CAR-T cells targetting the solid tumour, and potentially overcoming its immune suppression capabilities. This strategy could benefit from the combination with PD-1 inhibitors and low tumour loads. Our computational results provide theoretical support for the treatment of different types of solid tumours using T cells engineered with combination treatments of dual CARs with on- and off-tumour activity and anti-PD-1 drugs after completion of classical cytoreductive treatments. [ABSTRACT FROM AUTHOR]

Simple Summary: Prodrugs that increase the level of reactive oxygen species (ROS) specifically in cancer cells while not affecting normal cells can potentially act as radiosensitizers for side effect free radiotherapy (RT). However, previously known ROS-amplifying prodrugs were found to not beuseful for this purpose. Since functional mitochondria are necessary for RT-resistance, we assumed that the problem could be solved by using dual prodrugs as radiosensitizers, both targeting mitochondria and simultaneously inducing ROS. In this paper, we explored this possibility. In particular, we developed an N-alkylaminoferrocene-based prodrug (2c) effective at low μMolar concentrations. Upon conversion to its active form 2c_BA in aqueous solution, it is efficiently taken up by cancer cells. This leads to the decrease of their mitochondrial membrane potential and the amplification of both, intracellular mitochondrial and total ROS generation. We found that 2c_BA acts as an efficient radiosensitizer in human head and neck squamous carcinoma cells in vitro. Radiotherapy (RT) efficacy can be improved by using radiosensitizers, i.e., drugs enhancing the effect of ionizing radiation (IR). One of the side effects of RT includes damage of normal tissue in close proximity to the treated tumor. This problem can be solved by applying cancer specific radiosensitizers. N-Alkylaminoferrocene-based (NAAF) prodrugs produce reactive oxygen species (ROS) in cancer cells, but not in normal cells. Therefore, they can potentially act as cancer specific radiosensitizers. However, early NAAF prodrugs did not exhibit this property. Since functional mitochondria are important for RT resistance, we assumed that NAAF prodrugs affecting mitochondria in parallel with increasing intracellular ROS can potentially exhibit synergy with RT. We applied sequential Cu+-catalyzed alkyne-azide cycloadditions (CuAAC) to obtain a series of NAAF derivatives with the goal of improving anticancer efficacies over already existing compounds. One of the obtained prodrugs (2c) exhibited high anticancer activity with IC50 values in the range of 5–7.1 µM in human ovarian carcinoma, Burkitt's lymphoma, pancreatic carcinoma and T-cell leukemia cells retained moderate water solubility and showed cancer specificity. 2c strongly affects mitochondria of cancer cells, leading to the amplification of mitochondrial and total ROS production and thus causing cell death via necrosis and apoptosis. We observed that 2c acts as a radiosensitizer in human head and neck squamous carcinoma cells. This is the first demonstration of a synergy between the radiotherapy and NAAF-based ROS amplifiers. [ABSTRACT FROM AUTHOR]

Simple Summary: Mitochondria are well known for being the powerhouses of the cell—whether the cell is normal or cancerous. Moreover, they can move, split, fuse themselves, or be eliminated via mitophagy with the help of the interplay between motor proteins and the cell scaffold—especially microtubules. The relationship between mitochondria, microtubules, and motor proteins is altered in cancer, and targeting this molecular machinery can offer a novel weapon in its treatment. In this paper, we review and summarize the state of the art of this approach. Mitochondria constitute an ever-reorganizing dynamic network that plays a key role in several fundamental cellular functions, including the regulation of metabolism, energy production, calcium homeostasis, production of reactive oxygen species, and programmed cell death. Each of these activities can be found to be impaired in cancer cells. It has been reported that mitochondrial dynamics are actively involved in both tumorigenesis and metabolic plasticity, allowing cancer cells to adapt to unfavorable environmental conditions and, thus, contributing to tumor progression. The mitochondrial dynamics include fusion, fragmentation, intracellular trafficking responsible for redistributing the organelle within the cell, biogenesis, and mitophagy. Although the mitochondrial dynamics are driven by the cytoskeleton—particularly by the microtubules and the microtubule-associated motor proteins dynein and kinesin—the molecular mechanisms regulating these complex processes are not yet fully understood. More recently, an exchange of mitochondria between stromal and cancer cells has also been described. The advantage of mitochondrial transfer in tumor cells results in benefits to cell survival, proliferation, and spreading. Therefore, understanding the molecular mechanisms that regulate mitochondrial trafficking can potentially be important for identifying new molecular targets in cancer therapy to interfere specifically with tumor dissemination processes. [ABSTRACT FROM AUTHOR]

Simple Summary: Genome replication, repair, recombination, and the DNA damage response (DDR) rely on a cadre of DNA binding proteins to execute and regulate these critical pathways. There are many structural motifs that support DNA-binding and included in these is the oligonucleotide/oligosaccharide binding fold (OB-fold). OB-folds are found across the tree of life and play critical roles in chromosome maintenance and stability. This paper reviews the current state of knowledge regarding structure, function, and involvement of OB-fold proteins in the DNA damage response, replication, and repair. We highlight a group of OB-fold DNA binding proteins and discuss how disruption of these critical protein–DNA interactions can be exploited in cancer therapy. Genome stability and maintenance pathways along with their requisite proteins are critical for the accurate duplication of genetic material, mutation avoidance, and suppression of human diseases including cancer. Many of these proteins participate in these pathways by binding directly to DNA, and a subset employ oligonucleotide/oligosaccharide binding folds (OB-fold) to facilitate the protein–DNA interactions. OB-fold motifs allow for sequence independent binding to single-stranded DNA (ssDNA) and can serve to position specific proteins at specific DNA structures and then, via protein–protein interaction motifs, assemble the machinery to catalyze the replication, repair, or recombination of DNA. This review provides an overview of the OB-fold structural organization of some of the most relevant OB-fold containing proteins for oncology and drug discovery. We discuss their individual roles in DNA metabolism, progress toward drugging these motifs and their utility as potential cancer therapeutics. While protein–DNA interactions were initially thought to be undruggable, recent reports of success with molecules targeting OB-fold containing proteins suggest otherwise. The potential for the development of agents targeting OB-folds is in its infancy, but if successful, would expand the opportunities to impinge on genome stability and maintenance pathways for more effective cancer treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: In this systematic review, we aim to highlight existing literature devoted to the study of an association between medical imaging radiomics and cancer biological endpoints. The use of radiomics as an ancillary tool in cancer treatment would allow for a non-invasive, inexpensive, three-dimensional characterization of the tumor phenotype, contributing to the delivery of precision medicine. Nonetheless, its clinical application remains a challenge, as extensive, multi-center validation studies of radiomic features connection with tumor biology are required. In this review, we performed a search in PubMed database for peer-reviewed studies which evaluate the association between radiomic features and the following set of clinically relevant tumor markers: anaplastic lymphoma kinase (ALK), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), epidermal growth factor (EGFR), human epidermal growth factor receptor 2 (HER-2), isocitrate dehydrogenase (IDH), antigen Ki-67, kirsten rat sarcoma viral oncogene homolog (KRAS), programmed cell death ligand 1 (PD-L1), tumor protein p53 (TP-53) and vascular endothelial growth factor (VEGF). Radiomics supposes an alternative non-invasive tumor characterization tool, which has experienced increased interest with the advent of more powerful computers and more sophisticated machine learning algorithms. Nonetheless, the incorporation of radiomics in cancer clinical-decision support systems still necessitates a thorough analysis of its relationship with tumor biology. Herein, we present a systematic review focusing on the clinical evidence of radiomics as a surrogate method for tumor molecular profile characterization. An extensive literature review was conducted in PubMed, including papers on radiomics and a selected set of clinically relevant and commonly used tumor molecular markers. We summarized our findings based on different cancer entities, additionally evaluating the effect of different modalities for the prediction of biomarkers at each tumor site. Results suggest the existence of an association between the studied biomarkers and radiomics from different modalities and different tumor sites, even though a larger number of multi-center studies are required to further validate the reported outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: As for other neoplasms, liquid biopsy can be a useful tool to improve diagnosis and to monitor the response to therapy of high-grade serous epithelial ovarian cancer, which is the most common and lethal gynecological malignancy. In this paper, we provide an overview of the available knowledge on the current status and future opportunities by the analysis of tumor-derived components circulating in the blood of high-grade serous epithelial ovarian cancer patients. The lack of a sensitive and specific biomarker and the limits relating to the single primary tumor sampling make it difficult to monitor high-grade serous epithelial ovarian cancer (HGS-EOC) over time and to capture those alterations that are potentially useful in guiding clinical decisions. To overcome these issues, liquid biopsy has emerged as a very promising tool for HGS-EOC. The analysis of circulating tumor DNA appears to be feasible and studies assessing specific pathogenic mutations (i.e., TP53) or copy number alterations have shown a sufficient degree of sensitivity and specificity to be realistically used to monitor the effectiveness of antitumor therapy. Liquid biopsy can also provide potential important information on the mechanisms of sensitivity and resistance, e.g., by the determination of the reversion of BRCA mutations. Perspective studies are needed to test whether the application of liquid biopsy will significantly improve HGS-EOC management and patients' survival. [ABSTRACT FROM AUTHOR]

Simple Summary: The use of nanopharmaceuticals in chemotherapeutic regimens has become a promising approach for the treatment of most of the demanding types of cancers. Their in-depth physicochemical characterization plays an instrumental role in the quality control of a promising new medicine. The combined function of diagnosis and therapy in the same nanopharmaceuticals created the so-called nanotheragnostics, which have found a broad range of applications in this field. This review addresses the state of the art on the use of nanopharmaceuticals in cancer therapy and the latest challenges encountered in regulating these new medicines. Physicochemical, pharmacokinetic, and biopharmaceutical characterization tools play a key role in the assessment of nanopharmaceuticals' potential imaging analysis and for site-specific delivery of anti-cancers to neoplastic cells/tissues. If diagnostic tools and therapeutic approaches are combined in one single nanoparticle, a new platform called nanotheragnostics is generated. Several analytical technologies allow us to characterize nanopharmaceuticals and nanoparticles and their properties so that they can be properly used in cancer therapy. This paper describes the role of multifunctional nanoparticles in cancer diagnosis and treatment, describing how nanotheragnostics can be useful in modern chemotherapy, and finally, the challenges associated with the commercialization of nanoparticles for cancer therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune checkpoint inhibitors (ICIs) constitute a paradigm shift in cancer therapy, and it has greatly expanded our knowledge of anticancer immunity and has introduced breakthroughs in cancer therapy. However, despite the promising results in the use of immunotherapy in some cancers, numerous patients do not respond to ICIs without the existence of a clear predictive biomarker. This review provides an overview of recent advances in cellular and molecular factors within the tumor microenvironment (TME) to identify possible mechanisms of immunotherapy resistance, as well as to develop novel combination strategies for cancer immunotherapy. The in-depth exploration of complexity within the TME allows for the improvement of therapeutic efficacy and highlights its contribution to cancer immunotherapy. Immune checkpoints play critical roles in the regulation of T-cell effector function, and the effectiveness of their inhibitors in cancer therapy has been established. Immune checkpoint inhibitors (ICIs) constitute a paradigm shift in cancer therapy in general and cancer immunotherapy in particular. Immunotherapy has been indicated to reinvigorate antitumor T-cell activity and dynamically modulate anticancer immune responses. However, despite the promising results in the use of immunotherapy in some cancers, numerous patients do not respond to ICIs without the existence of a clear predictive biomarker. Overall, immunotherapy involves a certain degree of uncertainty and complexity. Research on the exploration of cellular and molecular factors within the tumor microenvironment (TME) aims to identify possible mechanisms of immunotherapy resistance, as well as to develop novel combination strategies involving the specific targeting of the TME for cancer immunotherapy. The combination of this approach with other types of treatment, including immune checkpoint blockade therapy involving multiple agents, most of the responses and effects in cancer therapy could be significantly enhanced, but the appropriate combinations have yet to be established. Moreover, the in-depth exploration of complexity within the TME allows for the exploration of pathways of immune dysfunction. It may also aid in the identification of new therapeutic targets. This paper reviews recent advances in the improvement of therapeutic efficacy on the immune context of the TME and highlights its contribution to cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Exercise is associated with many aspects of a healthy lifestyle. Among these, exercise leads to the secretion of adrenaline and noradrenaline, which mobilize cells of the immune system, a process which is suggested to possess therapeutic value in cancer therapy, alone or in combination with immunotherapy. Strikingly, administration of β-blockers—which block the effect of adrenaline/noradrenaline—are also suggested to be useful in cancer therapy alone or in combination with immunotherapy. Herein we discuss the question of whether exercise and the administration of β-blockers could potentially be useful in cancer therapy. The incidence of cancer is increasing worldwide, which is to a large extent related to the population's increasing lifespan. However, lifestyle changes in the Western world are causative as well. Exercise is intrinsically associated with what one could call a "healthy life", and physical activity is associated with a lower risk of various types of cancer. Mouse models of exercise have shown therapeutic efficacy across numerous cancer models, at least in part due to the secretion of adrenaline, which mobilizes cells of the immune system, i.e., cytotoxic T and natural killer (NK) cells, through signaling of the β-2 adrenergic receptor (β2AR). Clinical trials aiming to investigate the clinical value of exercise are ongoing. Strikingly, however, the use of β-blockers—antagonists of the very same signaling pathway—also shows signs of clinical potential in cancer therapy. Cancer cells also express β-adrenergic receptors (βARs) and signaling of the receptor is oncogenic. Moreover, there are data to suggest that β2AR signaling in T cells renders the cell functionally suppressed. In this paper, we discuss these seemingly opposing mechanisms of cancer therapy—exercise, which leads to increased β2AR signaling, and β-blocker treatment, which antagonizes that same signaling—and suggest potential mechanisms and possibilities for their combination. [ABSTRACT FROM AUTHOR]

Simple Summary: The aim of this review is to provide an overview of the current scientific evidence concerning the role played by exosomes in the pathogenesis, diagnosis and treatment of diseases. The potential use of exosomes as delivery vectors for small-molecule therapeutic agents will be discussed. In addition, a special emphasis will be placed on the involvement of exosomes in oncological diseases, as well as to their potential therapeutic application as liquid biopsy tools mainly in cancer diagnosis. A better understanding of exosome biology could improve the results of clinical interventions using exosomes as therapeutic agents. Exosomes are lipid bilayer particles released from cells into their surrounding environment. These vesicles are mediators of near and long-distance intercellular communication and affect various aspects of cell biology. In addition to their biological function, they play an increasingly important role both in diagnosis and as therapeutic agents. In this paper, we review recent literature related to the molecular composition of exosomes, paying special attention to their role in pathogenesis, along with their application as biomarkers and as therapeutic tools. In this context, we analyze the potential use of exosomes in biomedicine, as well as the limitations that preclude their wider application. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer immunotherapy is a breakthrough in cancer treatment. Unfortunately, despite the encouraging results in clinical treatment, cancer immunotherapy such as CAR-T, PD-1 still faces lots of challenges. Therefore, it is necessary to develop new methods to improve the effectiveness and safety of tumor immunotherapy. In recent years, cell membrane-coated nanomaterial is one of the most promising drug delivery systems and is receiving a great deal of attention due to its naturally biocompatible characteristics. This review summarizes the latest research progress, the advantages, the disadvantages, and the application of immunocyte membrane-coated nanoparticles in cancer immunotherapy. Despite the advances in surface bioconjugation of synthetic nanoparticles for targeted drug delivery, simple biological functionalization is still insufficient to replicate complex intercellular interactions naturally. Therefore, these foreign nanoparticles are inevitably exposed to the immune system, which results in phagocytosis by the reticuloendothelial system and thus, loss of their biological significance. Immunocyte membranes play a key role in intercellular interactions, and can protect foreign nanomaterials as a natural barrier. Therefore, biomimetic nanotechnology based on cell membranes has developed rapidly in recent years. This paper summarizes the development of immunocyte membrane-coated nanoparticles in the immunotherapy of tumors. We will introduce several immunocyte membrane-coated nanocarriers and review the challenges to their large-scale preparation and application. [ABSTRACT FROM AUTHOR]

Simple Summary: Multimodal imaging systems with high registration accuracy and molecular agents with highly specific targeting capacity are vital for imaging-guided theranostics of cancer. A novel simultaneous dual-modal imaging system combined with cancer cell membrane-coated nanoparticles as an imaging-guided photothermal therapy (PTT) was reported in this paper. A novel detector with the ability to detect both high-energy X-ray and low-energy visible light at the same time, as well as a dual-modal imaging system based on the detector, was developed for intrinsic simultaneous dual-modal imaging. Cancer cell membrane-coated upconversion nanoparticles (CC-UCNPs) and gold nanoparticles (CC-AuNPs) with the capacity for immune evasion and active tumor targeting were engineered for highly specific imaging and high-efficiency PTT therapy. The highly specific imaging-guided PTT efficacy was evaluated both in vitro and in vivo. All these results suggested our biomimetic UCNP/AuNP and novel simultaneous dual-modal imaging combination could be a promising platform and methodology for cancer theranostics. Multimodal imaging-guided near-infrared (NIR) photothermal therapy (PTT) is an interesting and promising cancer theranostic method. However, most of the multimodal imaging systems provide structural and functional information used for imaging guidance separately by directly combining independent imaging systems with different detectors, and many problems arise when trying to fuse different modal images that are serially taken by inviting extra markers or image fusion algorithms. Further, most imaging and therapeutic agents passively target tumors through the enhanced permeability and retention (EPR) effect, which leads to low utilization efficiency. To address these problems and systematically improve the performance of the imaging-guided PTT methodology, we report a novel simultaneous dual-modal imaging system combined with cancer cell membrane-coated nanoparticles as a platform for PTT-based cancer theranostics. A novel detector with the ability to detect both high-energy X-ray and low-energy visible light at the same time, as well as a dual-modal imaging system based on the detector, was developed for simultaneous dual-modal imaging. Cancer cell membrane-coated upconversion nanoparticles (CC-UCNPs) and gold nanoparticles (CC-AuNPs) with the capacity for immune evasion and active tumor targeting were engineered for highly specific imaging and high-efficiency PTT therapy. In vitro and in vivo evaluation of macrophage escape and active homologous tumor targeting were performed. Cancer cell membrane-coated nanoparticles (CC-NPs) displayed excellent immune evasion ability, longer blood circulation time, and higher tumor targeting specificity compared to normal PEGylated nanoparticles, which led to highly specific upconversion luminescence (UCL) imaging and PTT-based anti-tumor efficacy. The anti-cancer efficacy of the dual-modal imaging-guided PTT was also evaluated both in vitro and in vivo. Dual-modal imaging yielded precise anatomical and functional information for the PTT process, and complete tumor ablation was achieved with CC-AuNPs. Our biomimetic UCNP/AuNP and novel simultaneous dual-modal imaging combination could be a promising platform and methodology for cancer theranostics. [ABSTRACT FROM AUTHOR]

Simple Summary: DNA vaccination represents a useful approach for human papillomavirus (HPV) cancer therapy. The therapeutic potential of plant-based natural compounds for control of HPV- associated cancers has been also widely explored. Genetic vaccines for HPV-associated tumors that include plant protein-encoding gene sequences, used alone or in combinations with plant metabolites, are being investigated but are still in their infancy. Main focus of this paper is to provide an overview of the current state of novel therapeutic strategies employing genetic vaccines along with plant-derived compounds and genes. We highlight the importance of multimodality treatment regimen such as combining immunotherapy with plant-derived agents. Antigen-specific immunotherapy and, in particular, DNA vaccination provides an established approach for tackling human papillomavirus (HPV) cancers at different stages. DNA vaccines are stable and have a cost-effective production. Their intrinsic low immunogenicity has been improved by several strategies with some success, including fusion of HPV antigens with plant gene sequences. Another approach for the control of HPV cancers is the use of natural immunomodulatory agents like those derived from plants, that are able to interfere in carcinogenesis by modulating many different cellular pathways and, in some instances, to reduce chemo- and radiotherapy resistance of tumors. Indeed, plant-derived compounds represent, in many cases, an abundantly available, cost-effective source of molecules that can be either harvested directly in nature or obtained from plant cell cultures. In this review, an overview of the most relevant data reported in literature on the use of plant natural compounds and genetic vaccines that include plant-derived sequences against HPV tumors is provided. The purpose is also to highlight the still under-explored potential of multimodal treatments implying DNA vaccination along with plant-derived agents. [ABSTRACT FROM AUTHOR]

Simple Summary: Photodynamic therapy (PDT) has been undertaken with growing focus in recent studies to identify successful anticancer therapies. The field of PDT has evolved rapidly and is continuously being evaluated with new techniques. To make PDT more active and selective, molecular strategies are being developed. In the latest clinical studies on the use of PDT, some challenges are presented. Therefore, the use of nanotechnology-based approaches as delivery tools for PSs may improve their cancer cellular uptake and their toxic properties, as well as the PDT's therapeutic impact. In addition, photoimmunotherapy (PIT) and photothermal therapy (PTT) might have a significant impact on solid tumor therapeutic strategies. Current research to find effective anticancer treatments is being performed on photodynamic therapy (PDT) with increasing attention. PDT is a very promising therapeutic way to combine a photosensitive drug with visible light to manage different intense malignancies. PDT has several benefits, including better safety and lower toxicity in the treatment of malignant tumors over traditional cancer therapy. This reasonably simple approach utilizes three integral elements: a photosensitizer (PS), a source of light, and oxygen. Upon light irradiation of a particular wavelength, the PS generates reactive oxygen species (ROS), beginning a cascade of cellular death transformations. The positive therapeutic impact of PDT may be limited because several factors of this therapy include low solubilities of PSs, restricting their effective administration, blood circulation, and poor tumor specificity. Therefore, utilizing nanocarrier systems that modulate PS pharmacokinetics (PK) and pharmacodynamics (PD) is a promising approach to bypassing these challenges. In the present paper, we review the latest clinical studies and preclinical in vivo studies on the use of PDT and progress made in the use of nanotherapeutics as delivery tools for PSs to improve their cancer cellular uptake and their toxic properties and, therefore, the therapeutic impact of PDT. We also discuss the effects that photoimmunotherapy (PIT) might have on solid tumor therapeutic strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: Combination of radiotherapy and immunotherapy to antagonize tumors is one of hotspot issues currently. Immunotherapy can effectively alleviate the non-lasting effect of radiotherapy and tumor recurrence. Local radiotherapy can mobilize immune cells into tumor microenvironment and make tumors unable to escape from immune supervision. Therefore, the radio-immunotherapy achieves better curative effects on cancer patients. We have reviewed the regulation of multiple immune cells with different functions by radiotherapy, as well as the mechanism research and clinical outcomes combined with immune checkpoint inhibitors for cancer treatment, which provides new insights in the treatment strategies for certain types of cancer patients in clinic. Radiotherapy (RT) is a conventional method for clinical treatment of local tumors, which can induce tumor-specific immune response and cause the shrinkage of primary tumor and distal metastases via mediating tumor infiltration of CD8+ T cells. Ionizing radiation (IR) induced tumor regression outside the radiation field is termed as abscopal effect. However, due to the mobilization of immunosuppressive signals by IR, the activated CD8+T cells are not sufficient to maintain a long-term positive feedback to make the tumors regress completely. Eventually, the "hot" tumors gradually turn to "cold". With the advent of emerging immunotherapy, the combination of immune checkpoint blockade (ICB) and local RT has produced welcome changes in stubborn metastases, especially anti-PD-1/PD-L1 and anti-CTLA-4 which have been approved in clinical cancer treatment. However, the detailed mechanism of the abscopal effect induced by combined therapy is still unclear. Therefore, how to formulate a therapeutic schedule to maximize the efficacy should be took into consideration according to specific circumstance. This paper reviewed the recent research progresses in immunomodulatory effects of local radiotherapy on the tumor microenvironment, as well as the unique advantage for abscopal effect when combined with ICB, with a view to exploring the potential application value of radioimmunotherapy in clinic. [ABSTRACT FROM AUTHOR]

Photochemical internalization (PCI) is a further development of photodynamic therapy (PDT). In this report, we describe PCI as a potential tool for cellular internalization of chemotherapeutic agents or antigens and systematically review the ongoing research. Eighteen published papers described the pre-clinical and clinical developments of PCI-mediated delivery of chemotherapeutic agents or antigens. The studies were screened against pre-defined eligibility criteria. Pre-clinical studies suggest that PCI can be effectively used to deliver chemotherapeutic agents to the cytosol of tumor cells and, thereby, improve treatment efficacy. One Phase-I clinical trial has been conducted, and it demonstrated that PCI-mediated bleomycin treatment was safe and identified tolerable doses of the photosensitizer disulfonated tetraphenyl chlorin (TPCS2a). Likewise, PCI was pre-clinically shown to mediate major histocompatibility complex (MHC) class I antigen presentation and generation of tumor-specific cytotoxic CD8+ T-lymphocytes (CTL) and cancer remission. A first clinical Phase I trial with the photosensitizer TPCS2a combined with human papilloma virus antigen (HPV) was recently completed and results are expected in 2020. Hence, photosensitizers and light can be used to mediate cytosolic delivery of endocytosed chemotherapeutics or antigens. While the therapeutic potential in cancer has been clearly demonstrated pre-clinically, further clinical trials are needed to reveal the true translational potential of PCI in humans. [ABSTRACT FROM AUTHOR]

Since the clear demonstration of lysophosphatidic acid (LPA)'s pathological roles in cancer in the mid-1990s, more than 1000 papers relating LPA to various types of cancer were published. Through these studies, LPA was established as a target for cancer. Although LPA-related inhibitors entered clinical trials for fibrosis, the concept of targeting LPA is yet to be moved to clinical cancer treatment. The major challenges that we are facing in moving LPA application from bench to bedside include the intrinsic and complicated metabolic, functional, and signaling properties of LPA, as well as technical issues, which are discussed in this review. Potential strategies and perspectives to improve the translational progress are suggested. Despite these challenges, we are optimistic that LPA blockage, particularly in combination with other agents, is on the horizon to be incorporated into clinical applications. [ABSTRACT FROM AUTHOR]

Early observations showed a lack of growth control and terminal differentiation with a lack of gap junctional intercellular communication (GJIC). Subsequent observations showed that epigenetic tumor promoters and activated oncogenes, which block gap junction function, provide insights into the multi-stage, multi-mechanism carcinogenic process. With the isolation of embryonic induced pluri-potent stem cells and organ-specific adult stem cells, gap junctions were linked to early development. While tumors and tumor cell lines are a heterogeneous mixture of "cancer stem cells" and "cancer non-stem cells", the cancer stem cells seem to be of two types, namely, they express (a) no connexin genes or (b) connexin genes, but do not have functional GJIC. These observations suggest that these "cancer stem cells" originate from normal adult stem cells or from the de-differentiation or re-programming of somatic differentiated cells. This "Concept Paper" provides a hypothesis that "cancer stem cells" either originate from (a) organ-specific adult stem cells before the expression of the connexin genes or (b) organ-specific adult stem cells that just express gap junction genes but that the connexin proteins are rendered dysfunctional by activated oncogenes. Therefore, cancer prevention and therapeutic strategies must account for these two different types of "cancer stem cell". [ABSTRACT FROM AUTHOR]

Neuroendocrine tumors (NETs) are a group of malignancies that originated from neuroendocrine cells, with the most common sites being lungs and the gastrointestinal tract. Lung NETs comprise 25% of all lung malignancies. Small cell lung cancer is the most common form of lung NETs, and other rare forms include well-differentiated typical carcinoids (TCs) and poorly differentiated atypical carcinoids (ACs). Given the paucity of randomized studies, rational treatment is challenging. Therefore, it is recommended that these decisions be made using a multidisciplinary collaborative approach. Surgery remains the mainstay of treatment, when feasible. Following surgery, various guidelines offer different recommendations in the adjuvant setting. In this paper, we describe the adjuvant management of lung NETs, as recommended by different guidelines, and highlight their differences. In addition to that, we also discuss the management of metastatic lung NETS, including the use of peptide receptor radionucleotide therapy. [ABSTRACT FROM AUTHOR]