A novel view of ferritin in cancer.

Since its discovery more than 85 years ago, ferritin has principally been known as an iron storage protein. However, new roles, beyond iron storage, are being uncovered. Novel processes involving ferritin such as ferritinophagy and ferroptosis and as a cellular iron delivery protein not only expand our thinking on the range of contributions of this protein but present an opportunity to target these pathways in cancers. The key question we focus on within this review is whether ferritin modulation represents a useful approach for treating cancers. We discussed novel functions and processes of this protein in cancers. We are not limiting this review to cell intrinsic modulation of ferritin in cancers, but also focus on its utility in the trojan horse approach in cancer therapeutics. The novel functions of ferritin as discussed herein realize the multiple roles of ferritin in cell biology that can be probed for therapeutic opportunities and further research.

Plant-Derived Extracellular Vesicles and Their Exciting Potential as the Future of Next-Generation Drug Delivery.

Plant cells release tiny membranous vesicles called extracellular vesicles (EVs), which are rich in lipids, proteins, nucleic acids, and pharmacologically active compounds. These plant-derived EVs (PDEVs) are safe and easily extractable and have been shown to have therapeutic effects against inflammation, cancer, bacteria, and aging. They have shown promise in preventing or treating colitis, cancer, alcoholic liver disease, and even COVID-19. PDEVs can also be used as natural carriers for small-molecule drugs and nucleic acids through various administration routes such as oral, transdermal, or injection. The unique advantages of PDEVs make them highly competitive in clinical applications and preventive healthcare products in the future. This review covers the latest methods for isolating and characterizing PDEVs, their applications in disease prevention and treatment, and their potential as a new drug carrier, with special attention to their commercial viability and toxicological profile, as the future of nanomedicine therapeutics. This review champions the formation of a new task force specializing in PDEVs to address a global need for rigor and standardization in PDEV research.

Oxidative Stress Linking Obesity and Cancer: Is Obesity a 'Radical Trigger' to Cancer?

Obesity is on the rise worldwide, and consequently, obesity-related non-communicable diseases are as well. Nutritional overload induces metabolic adaptations in an attempt to restore the disturbed balance, and the byproducts of the mechanisms at hand include an increased generation of reactive species. Obesity-related oxidative stress causes damage to vulnerable systems and ultimately contributes to neoplastic transformation. Dysfunctional obese adipose tissue releases cytokines and induces changes in the cell microenvironment, promoting cell survival and progression of the transformed cancer cells. Other than the increased risk of cancer development, obese cancer patients experience higher mortality rates and reduced therapy efficiency as well. The fact that obesity is considered the second leading preventable cause of cancer prioritizes the research on the mechanisms connecting obesity to cancerogenesis and finding the solutions to break the link. Oxidative stress is integral at different stages of cancer development and advancement in obese patients. Hypocaloric, balanced nutrition, and structured physical activity are some tools for relieving this burden. However, the sensitivity of simultaneously treating cancer and obesity poses a challenge. Further research on the obesity-cancer liaison would offer new perspectives on prevention programs and treatment development.

Immunometabolic interference between cancer and COVID-19.

Even though cancer patients are generally considered more susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the mechanisms driving their predisposition to severe forms of coronavirus disease 2019 (COVID-19) have not yet been deciphered. Since metabolic disorders are associated with homeostatic frailty, which increases the risk of infection and cancer, we asked whether we could identify immunometabolic pathways intersecting with cancer and SARS-CoV-2 infection. Thanks to a combined flow cytometry and multiomics approach, here we show that the immunometabolic traits of COVID-19 cancer patients encompass alterations in the frequency and activation status of circulating myeloid and lymphoid subsets, and that these changes are associated with i) depletion of tryptophan and its related neuromediator tryptamine, ii) accumulation of immunosuppressive tryptophan metabolites (i.e., kynurenines), and iii) low nicotinamide adenine dinucleotide (NAD+) availability. This metabolic imbalance is accompanied by altered expression of inflammatory cytokines in peripheral blood mononuclear cells (PBMCs), with a distinctive downregulation of IL-6 and upregulation of IFNγ mRNA expression levels. Altogether, our findings indicate that cancer not only attenuates the inflammatory state in COVID-19 patients but also contributes to weakening their precarious metabolic state by interfering with NAD+-dependent immune homeostasis.

The Role of Lymphocyte Subsets, PD-1, and FAS (CD95) in COVID-19 Cancer Patients.

Lymphocytes are the main orchestrators that regulate the immune response in SARS-COV-2 infection. The exhaustion of T lymphocytes is a contributing factor to lymphopenia, which is responsible for the COVID-19 adverse outcome. However, it is still not demonstrated on a large scale, including cancer patients. Peripheral blood samples were obtained from 83 SARS-CoV2 infected cancer patients, and 29 COVID-19 infected noncancer patients compared to 28 age-matched healthy controls. Lymphocyte subsets were assessed for CD3, CD4, CD8, CD56, PD-1, and CD95 using flow cytometry. The data were correlated to the patients' clinical features, COVID-19 severity and outcomes. Lymphopenia, and decreased CD4+ T cells and CD8+ T cells were significantly observed in COVID-19 cancer and noncancer patients compared to the control group (p < 0.001, for all). There was a significantly increased expression of CD95 and PD-1 on the NK cells, CD4+ T cells, and CD8+ T cells in COVID-19 cancer and noncancer patients in comparison to the control group. The increased expression of CD95 on CD8+ T cells, as well as the increased expression of PD-1 on CD8+ T cells and NK cells are significantly associated with the severity of COVID-19 infection in cancer patients. The increased expression of CD95 and PD-1 on the CD4+ T cells, CD8+ T cells, and NK cells was observed significantly in nonsurviving patients and those who were admitted to the intensive care unit in COVID-19 cancer and noncancer patients. The increased expression of PD-1 and CD95 could be possible prognostic factors for COVID-19 severity and adverse outcomes in COVID-19 cancer and noncancer patients.

Metabolic Regulation of Inflammation and Its Resolution: Current Status, Clinical Needs, Challenges, and Opportunities.

Metabolism and inflammation have been viewed as two separate processes with distinct but critical functions for our survival: metabolism regulates the utilization of nutrients, and inflammation is responsible for defense and repair. Both respond to an organism's stressors to restore homeostasis. The interplay between metabolic status and immune response (immunometabolism) plays an important role in maintaining health or promoting disease development. Understanding these interactions is critical in developing tools for facilitating novel preventative and therapeutic approaches for diseases, including cancer. This trans-National Institutes of Health workshop brought together basic scientists, technology developers, and clinicians to discuss state-of-the-art, innovative approaches, challenges, and opportunities to understand and harness immunometabolism in modulating inflammation and its resolution.

Chemistry and biology of ferritin.

Iron is an essential element required by cells and has been described as a key player in ferroptosis. Ferritin operates as a fundamental iron storage protein in cells forming multimeric assemblies with crystalline iron cores. We discuss the latest findings on ferritin structure and activity and its link to cell metabolism and ferroptosis. The chemistry of iron, including its oxidation states, is important for its biological functions, its reactivity, and the biology of ferritin. Ferritin can be localized in different cellular compartments and secreted by cells with a variety of functions depending on its spatial context. Here, we discuss how cellular ferritin localization is tightly linked to its function in a tissue-specific manner, and how impairment of iron homeostasis is implicated in diseases, including cancer and coronavirus disease 2019. Ferritin is a potential biomarker and we discuss latest research where it has been employed for imaging purposes and drug delivery.

Emerging Roles of SIRT5 in Metabolism, Cancer, and SARS-CoV-2 Infection.

Sirtuin 5 (SIRT5) is a predominantly mitochondrial enzyme catalyzing the removal of glutaryl, succinyl, malonyl, and acetyl groups from lysine residues through a NAD+-dependent deacylase mechanism. SIRT5 is an important regulator of cellular homeostasis and modulates the activity of proteins involved in different metabolic pathways such as glycolysis, tricarboxylic acid (TCA) cycle, fatty acid oxidation, electron transport chain, generation of ketone bodies, nitrogenous waste management, and reactive oxygen species (ROS) detoxification. SIRT5 controls a wide range of aspects of myocardial energy metabolism and plays critical roles in heart physiology and stress responses. Moreover, SIRT5 has a protective function in the context of neurodegenerative diseases, while it acts as a context-dependent tumor promoter or suppressor. In addition, current research has demonstrated that SIRT5 is implicated in the SARS-CoV-2 infection, although opposing conclusions have been drawn in different studies. Here, we review the current knowledge on SIRT5 molecular actions under both healthy and diseased settings, as well as its functional effects on metabolic targets. Finally, we revise the potential of SIRT5 as a therapeutic target and provide an overview of the currently reported SIRT5 modulators, which include both activators and inhibitors.

Biomimetic cell-derived nanocarriers in cancer research.

Nanoparticles have now long demonstrated capabilities that make them attractive to use in biology and medicine. Some of them, such as lipid nanoparticles (SARS-CoV-2 vaccines) or metallic nanoparticles (contrast agents) are already approved for their use in the clinic. However, considering the constantly growing body of different formulations and the huge research around nanomaterials the number of candidates reaching clinical trials or being commercialized is minimal. The reasons behind being related to the "synthetic" and "foreign" character of their surface. Typically, nanomaterials aiming to develop a function or deliver a cargo locally, fail by showing strong off-target accumulation and generation of adverse responses, which is connected to their strong recognition by immune phagocytes primarily. Therefore, rendering in negligible numbers of nanoparticles developing their intended function. While a wide range of coatings has been applied to avoid certain interactions with the surrounding milieu, the issues remained. Taking advantage of the natural cell membranes, in an approach that resembles a cell transfer, the use of cell-derived surfaces has risen as an alternative to artificial coatings or encapsulation methods. Biomimetic technologies are based on the use of isolated natural components to provide autologous properties to the nanoparticle or cargo being encapsulated, thus, improving their therapeutic behavior. The main goal is to replicate the (bio)-physical properties and functionalities of the source cell and tissue, not only providing a stealthy character to the core but also taking advantage of homotypic properties, that could prove relevant for targeted strategies. Such biomimetic formulations have the potential to overcome the main issues of approaches to provide specific features and identities synthetically. In this review, we provide insight into the challenges of nano-biointerfaces for drug delivery; and the main applications of biomimetic materials derived from specific cell types, focusing on the unique strengths of the fabrication of novel nanotherapeutics in cancer therapy.

Adenoviral-based vaccine promotes neoantigen-specific CD8+ T cell stemness and tumor rejection.

Upon chronic antigen exposure, CD8+ T cells become exhausted, acquiring a dysfunctional state correlated with the inability to control infection or tumor progression. In contrast, stem-like CD8+ T progenitors maintain the ability to promote and sustain effective immunity. Adenovirus (Ad)-vectored vaccines encoding tumor neoantigens have been shown to eradicate large tumors when combined with anti-programmed cell death protein 1 (αPD-1) in murine models; however, the mechanisms and translational potential have not yet been elucidated. Here, we show that gorilla Ad vaccine targeting tumor neoepitopes enhances responses to αPD-1 therapy by improving immunogenicity and antitumor efficacy. Single-cell RNA sequencing demonstrated that the combination of Ad vaccine and αPD-1 increased the number of murine polyfunctional neoantigen-specific CD8+ T cells over αPD-1 monotherapy, with an accumulation of Tcf1+ stem-like progenitors in draining lymph nodes and effector CD8+ T cells in tumors. Combined T cell receptor (TCR) sequencing analysis highlighted a broader spectrum of neoantigen-specific CD8+ T cells upon vaccination compared to αPD-1 monotherapy. The translational relevance of these data is supported by results obtained in the first 12 patients with metastatic deficient mismatch repair (dMMR) tumors vaccinated with an Ad vaccine encoding shared neoantigens. Expansion and diversification of TCRs were observed in post-treatment biopsies of patients with clinical response, as well as an increase in tumor-infiltrating T cells with an effector memory signature. These findings indicate a promising mechanism to overcome resistance to PD-1 blockade by promoting immunogenicity and broadening the spectrum and magnitude of neoantigen-specific T cells infiltrating tumors.

Regulation of Cell Signaling Pathways and Non-Coding RNAs by Baicalein in Different Cancers.

Landmark discoveries in molecular oncology have provided a wide-angle overview of the heterogenous and therapeutically challenging nature of cancer. The power of modern 'omics' technologies has enabled researchers to deeply and comprehensively characterize molecular mechanisms underlying cellular functions. Interestingly, high-throughput technologies have opened new horizons for the design and scientific fool-proof evaluation of the pharmacological properties of targeted chemical compounds to tactfully control the activities of the oncogenic protein networks. Groundbreaking discoveries have galvanized the expansion of the repertoire of available pharmacopoeia to therapeutically target a myriad of deregulated oncogenic pathways. Natural product research has undergone substantial broadening, and many of the drugs which constitute the backbone of modern pharmaceuticals have been derived from the natural cornucopia. Baicalein has gradually gained attention because of its unique ability to target different oncogenic signal transduction cascades in various cancers. We have partitioned this review into different sub-sections to provide a broader snapshot of the oncogenic pathways regulated by baicalein. In this review, we summarize baicalein-mediated targeting of WNT/ß-catenin, AKT/mTOR, JAK/STAT, MAPK, and NOTCH pathways. We also critically analyze how baicalein regulates non-coding RNAs (microRNAs and long non-coding RNAs) in different cancers. Finally, we conceptually interpret baicalein-mediated inhibition of primary and secondary growths in xenografted mice.

White Blood Cell Membrane-Coated Nanoparticles: Recent Development and Medical Applications.

White blood cells (WBCs) are immune cells that play essential roles in critical diseases including cancers, infections, and inflammatory disorders. Their dynamic and diverse functions have inspired the development of WBC membrane-coated nanoparticles (denoted "WBC-NPs"), which are formed by fusing the plasma membranes of WBCs, such as macrophages, neutrophils, T cells, and natural killer cells, onto synthetic nanoparticle cores. Inheriting the entire source cell antigens, WBC-NPs act as source cell decoys and simulate their broad biointerfacing properties with intriguing therapeutic potentials. Herein, the recent development and medical applications of WBC-NPs focusing on four areas, including WBC-NPs as carriers for drug delivery, as countermeasures for biological neutralization, as nanovaccines for immune modulation, and as tools for the isolation of circulating tumor cells and fundamental research is reviewed. Overall, the recent development and studies of WBC-NPs have established the platform as versatile nanotherapeutics and tools with broad medical application potentials.

Endocytic trafficking of GAS6-AXL complexes is associated with sustained AKT activation.

AXL, a TAM receptor tyrosine kinase (RTK), and its ligand growth arrest-specific 6 (GAS6) are implicated in cancer metastasis and drug resistance, and cellular entry of viruses. Given this, AXL is an attractive therapeutic target, and its inhibitors are being tested in cancer and COVID-19 clinical trials. Still, astonishingly little is known about intracellular mechanisms that control its function. Here, we characterized endocytosis of AXL, a process known to regulate intracellular functions of RTKs. Consistent with the notion that AXL is a primary receptor for GAS6, its depletion was sufficient to block GAS6 internalization. We discovered that upon receptor ligation, GAS6-AXL complexes were rapidly internalized via several endocytic pathways including both clathrin-mediated and clathrin-independent routes, among the latter the CLIC/GEEC pathway and macropinocytosis. The internalization of AXL was strictly dependent on its kinase activity. In comparison to other RTKs, AXL was endocytosed faster and the majority of the internalized receptor was not degraded but rather recycled via SNX1-positive endosomes. This trafficking pattern coincided with sustained AKT activation upon GAS6 stimulation. Specifically, reduced internalization of GAS6-AXL upon the CLIC/GEEC downregulation intensified, whereas impaired recycling due to depletion of SNX1 and SNX2 attenuated AKT signaling. Altogether, our data uncover the coupling between AXL endocytic trafficking and AKT signaling upon GAS6 stimulation. Moreover, our study provides a rationale for pharmacological inhibition of AXL in antiviral therapy as viruses utilize GAS6-AXL-triggered endocytosis to enter cells.

Immunometabolism of Myeloid-Derived Suppressor Cells: Implications for Mycobacterium tuberculosis Infection and Insights from Tumor Biology.

The field of immunometabolism seeks to decipher the complex interplay between the immune system and the associated metabolic pathways. The role of small molecules that can target specific metabolic pathways and subsequently alter the immune landscape provides a desirable platform for new therapeutic interventions. Immunotherapeutic targeting of suppressive cell populations, such as myeloid-derived suppressor cells (MDSC), by small molecules has shown promise in pathologies such as cancer and support testing of similar host-directed therapeutic approaches in MDSC-inducing conditions such as tuberculosis (TB). MDSC exhibit a remarkable ability to suppress T-cell responses in those with TB disease. In tumors, MDSC exhibit considerable plasticity and can undergo metabolic reprogramming from glycolysis to fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS) to facilitate their immunosuppressive functions. In this review we look at the role of MDSC during M. tb infection and how their metabolic reprogramming aids in the exacerbation of active disease and highlight the possible MDSC-targeted metabolic pathways utilized during M. tb infection, suggesting ways to manipulate these cells in search of novel insights for anti-TB therapies.

Metabolic programs tailor T cell immunity in viral infection, cancer, and aging.

Productive T cell responses to infection and cancer rely on coordinated metabolic reprogramming and epigenetic remodeling among the immune cells. In particular, T cell effector and memory differentiation, exhaustion, and senescence/aging are tightly regulated by the metabolism-epigenetics axis. In this review, we summarize recent advances of how metabolic circuits combined with epigenetic changes dictate T cell fate decisions and shape their functional states. We also discuss how the metabolic-epigenetic axis orchestrates T cell exhaustion and explore how physiological factors, such as diet, gut microbiota, and the circadian clock, are integrated in shaping T cell epigenetic modifications and functionality. Furthermore, we summarize key features of the senescent/aged T cells and discuss how to ameliorate vaccination- and COVID-induced T cell dysfunctions by metabolic modulations. An in-depth understanding of the unexplored links between cellular metabolism and epigenetic modifications in various physiological or pathological contexts has the potential to uncover novel therapeutic strategies for fine-tuning T cell immunity.

Extracellular Vesicles: New Tools for Early Diagnosis of Breast and Genitourinary Cancers.

Breast cancers and cancers of the genitourinary tract are the most common malignancies among men and women and are still characterized by high mortality rates. In order to improve the outcomes, early diagnosis is crucial, ideally by applying non-invasive and specific biomarkers. A key role in this field is played by extracellular vesicles (EVs), lipid bilayer-delimited structures shed from the surface of almost all cell types, including cancer cells. Subcellular structures contained in EVs such as nucleic acids, proteins, and lipids can be isolated and exploited as biomarkers, since they directly stem from parental cells. Furthermore, it is becoming even more evident that different body fluids can also serve as sources of EVs for diagnostic purposes. In this review, EV isolation and characterization methods are described. Moreover, the potential contribution of EV cargo for diagnostic discovery purposes is described for each tumor.

Cytokines and Chemokines in Cancer Cachexia and Its Long-Term Impact on COVID-19.

Cancer cachexia remains a serious public health concern worldwide, particularly as cancer rates rise. Treatment is endangered, and survival is reduced, because this illness is commonly misdiagnosed and undertreated. Although weight loss is the most evident sign of cachexia, there are other early metabolic and inflammatory changes that occur before the most obvious symptoms appear. Cachexia-related inflammation is induced by a combination of factors, one of which is the release of inflammation-promoting chemicals by the tumor. Today, more scientists are beginning to believe that the development of SARS-CoV-2 (COVID-19) related cachexia is similar to cancer-related cachexia. It is worth noting that patients infected with COVID-19 have a significant inflammatory response and can develop cachexia. These correlations provide feasible reasons for the variance in the occurrence and severity of cachexia in human malignancies, therefore, specific therapeutic options for these individuals must be addressed based on disease types. In this review, we highlighted the role of key chemokines, cytokines, and clinical management in relation to cancer cachexia and its long-term impact on COVID-19 patients.

Incidental Findings Suggestive of COVID-19 Pneumonia in Oncologic Patients Undergoing 18F-FDG PET/CT Studies: Association Between Metabolic and Structural Lung Changes.

Although the novel coronavirus disease 2019 (COVID-19) can present as nonspecific clinical forms, subclinical cases represent an important route of transmission and a significant source of mortality, mainly in high-risk subpopulations such as cancer patients. A deeper knowledge of the metabolic shift in cells infected with severe acute respiratory syndrome coronavirus 2 could provide new insights about its pathogenic and host response and help to diagnose pulmonary involvement. We explored the potential added diagnostic value of 18F-FDG PET/CT scans in asymptomatic cancer patients with suspected COVID-19 pneumonia by investigating the association between metabolic and structural changes in the lung parenchyma. Methods:18F-FDG PET/CT studies acquired between February 19 and May 29, 2020, were reviewed to identify those cancer patients with incidental findings suggestive of COVID-19 pneumonia. PET studies were interpreted through qualitative (visual) and semiquantitative (measurement of SUVmax) analysis evaluating lung findings. Several characteristic signs of COVID-19 pneumonia on CT were described as COVID-19 Reporting and Data System (CO-RADS) categories (1-6). After comparing the SUVmax of pulmonary infiltrates among different CO-RADS categories, we explored the best potential cutoffs for pulmonary SUVmax against CO-RADS categories as the gold standard result to eliminate the possibility that the diagnosis of COVID-19 pneumonia exists. Results: On multimodal PET/CT imaging, CT signs classified as CO-RADS category 5 or 6 were found in 16 of 41 (39%) oncologic patients. SUVmax was higher in patients with categories 5 and 6 than in patients with category 4 (6.17 ± 0.82 vs. 3.78 ± 0.50, P = 0.04) or categories 2 and 3 (3.59 ± 0.41, P = 0.01). A specificity of 93.8% (95% CI, 71.7%-99.7%) and an accuracy of 92.9% were obtained when combining a CO-RADS score of 5 or 6 with an SUVmax of 2.45 in pulmonary infiltrates. Conclusion: In asymptomatic cancer patients, the metabolic activity in lung infiltrates is closely associated with several combined tomographic changes characteristic of COVID-19 pneumonia. Multimodal 18F-FDG PET/CT imaging could provide additional information during early diagnosis in selected predisposed patients during the pandemic. The prognostic implications of simultaneous radiologic and molecular findings in cancer patients and other subpopulations at high risk for COVID-19 pneumonia deserve further evaluation in prospective research.