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For decades, great strides have been made in the field of immunometabolism. A plethora of evidence ranging from basic mechanisms to clinical transformation has gradually embarked on immunometabolism to the center stage of innate and adaptive immunomodulation. Given this, we focus on changes in immunometabolism, a converging series of biochemical events that alters immune cell function, propose the immune roles played by diversified metabolic derivatives and enzymes, emphasize the key metabolism-related checkpoints in distinct immune cell types, and discuss the ongoing and upcoming realities of clinical treatment. It is expected that future research will reduce the current limitations of immunotherapy and provide a positive hand in immune responses to exert a broader therapeutic role. Highlights 1. Attempting to delineate the complex and multidimensional interplays between metabolites (or metabolic enzymes) and predominant immune cell populations. 2. Metabolic checkpoints of immune cells are described and the contribution of these metabolic targets to determine the metabolic adaptations of distinct immune cells in specific tissue environments is emphasized. 3. Proposed cancer-immunometabolism subcycle, enriching the theoretical foundation of the cancer-immunology field. 4. Metabolism-induced disturbances in the acid-base balance of the tumor microenvironment have non-redundant effects on immunotherapy. 5. Pending challenges and clinical concerns in metabolic insights were addressed.

IntroductionInvariant NKT (iNKT) cells are crucial effectors in cancer immunosurveillance, due to their immunomodulatory potential through a broad range of effector and regulatory functions. Yet, their use as targets or vectors for cancer immunotherapy in cancer yielded inconsistent outcomes, due to potential tumor immune escape mechanisms. Limited information is available regarding the potential dysfunctions of iNKT cells in melanoma patients, and their clinical significance. A better understanding of iNKT cell biology and subversion in these patients would help designing new immunotherapies and improving clinical translations.MethodsHere, we depicted extensive phenotypic, metabolic and functional features of circulating and tumor-infiltrating iNKT cells in melanoma patients, and assessed their clinical relevance.ResultsWe observed that iNKT cells infiltrated melanoma tumors in a gender- and site-dependent manner, and were associated with poor clinical outcome. Invariant NKT cells exhibited a higher basal activation status together with a skewed expression of NK receptors (NKR), NKG2 and immune checkpoints (ICP), as well as a shift toward regulatory iNKT (iNKTreg) cell profile in the melanoma microenvironment. We identified LAG3, CTLA4 and TIM3 as critical negative prognosis factors of clinical evolution. Moreover, tumor-infiltrating iNKT cells displayed a dampened metabolic activity with a decreased glycolysis dependency; such perturbed energetic metabolism impacted patient clinical outcome. Furthermore, iNKT cells revealed distinct metabolic profiles depending on their activation status and ICP profile, underlining critical connections between iNKT cell features and metabolic pattern.DiscussionOverall, our study reveals major phenotypic and metabolic disturbances of circulating and tumor-infiltrating iNKT cells in melanoma, with clinical impacts. By unveiling new key features and skewing details on iNKT cells in melanoma, our study paves the way for innovative combination strategies exploiting metabolic pathways and/or disturbed ICP profiles to overcome immune subversion and better harness the potential of iNKT cells for cancer immunotherapy.

A growing body of evidence indicates that, over the course of evolution of the immune system, arginine has been selected as a node for the regulation of immune responses. An appropriate supply of arginine has long been associated with the improvement of immune responses. In addition to being a building block for protein synthesis, arginine serves as a substrate for distinct metabolic pathways that profoundly affect immune cell biology; especially macrophage, dendritic cell and T cell immunobiology. Arginine availability, synthesis, and catabolism are highly interrelated aspects of immune responses and their fine-tuning can dictate divergent pro-inflammatory or anti-inflammatory immune outcomes. Here, we review the organismal pathways of arginine metabolism in humans and rodents, as essential modulators of the availability of this semi-essential amino acid for immune cells. We subsequently review well-established and novel findings on the functional impact of arginine biosynthetic and catabolic pathways on the main immune cell lineages. Finally, as arginine has emerged as a molecule impacting on a plethora of immune functions, we integrate key notions on how the disruption or perversion of arginine metabolism is implicated in pathologies ranging from infectious diseases to autoimmunity and cancer.

The immune system is the most important protective physiological system of the organism. It has many connections with other systems and is, in fact, often considered as part of the larger neuro-endocrine-immune axis. Most experimental data on immune changes with aging show a decline in many immune parameters when compared to young healthy subjects. The bulk of these changes is termed immunosenescence. Immunosenescence has been considered for some time as detrimental because it often leads to subclinical accumulation of pro-inflammatory factors and inflamm-aging. Together, immunosenescence and inflamm-aging are suggested to stand at the origin of most of the diseases of the elderly, such as infections, cancer, autoimmune disorders, and chronic inflammatory diseases. However, an increasing number of immune-gerontologists have challenged this negative interpretation of immunosenescence with respect to its significance in aging-related alterations of the immune system. If one considers these changes from an evolutionary perspective, they can be viewed preferably as adaptive or remodeling rather than solely detrimental. Whereas it is conceivable that global immune changes may lead to various diseases, it is also obvious that these changes may be needed for extended survival/longevity. Recent cumulative data suggest that, without the existence of the immunosenescence/inflamm-aging duo (representing two sides of the same phenomenon), human longevity would be greatly shortened. This review summarizes recent data on the dynamic reassessment of immune changes with aging. Accordingly, attempts to intervene on the aging immune system by targeting its rejuvenation, it may be more suitable to aim to maintain general homeostasis and function by appropriately improving immune-inflammatory-functions.

Malnutrition refers to a person’s status as under- or overnourished, and it is usually associated with an inflammation status, which can subsequently imply a different health status, as the risk of infection is increased, along with a deterioration of the immune system. Children’s immune systems are generally more susceptible to problems than adults. In the situation of malnutrition, because malnourished children’s immune systems are compromised, they are more likely to die. However, little is known about the underlying mechanism of altered immune functioning and how it relates to starvation. Nutritional interventions have been reported as cost-effective strategies to prevent or treat the development of malnourishment, considering the link between food intake and health, especially in children, and also the susceptibility of this population to diseases and how their health status during childhood might affect their long-term physiological growth. The ingestion of specific nutrients (e.g., vitamins or oligoelements) has been reported to contribute to the proper functioning of children’s immune systems. In this review, we aim to describe the basis of malnutrition and how this is linked to the immune system, considering the role of nutrients in the modulation of the immune system and the risk of infection that can occur in these situations in children, as well as to identify nutritional interventions to improve their health.

In response to inflammatory activation by pathogens, macrophages accumulate triglycerides in intracellular lipid droplets. The mechanisms underlying triglyceride accumulation and its exact role in the inflammatory response of macrophages are not fully understood. Here, we aim to further elucidate the mechanism and function of triglyceride accumulation in the inflammatory response of activated macrophages. Lipopolysaccharide (LPS)-mediated activation markedly increased triglyceride accumulation in macrophages. This increase could be attributed to up-regulation of the hypoxiainducible lipid droplet–associated (HILPDA) protein, which down-regulated adipose triglyceride lipase (ATGL) protein levels, in turn leading to decreased ATGL-mediated triglyceride hydrolysis. The reduction in ATGL-mediated lipolysis attenuated the inflammatory response in macrophages after ex vivo and in vitro activation, and was accompanied by decreased production of prostaglandin-E2 (PGE2) and interleukin-6 (IL-6). Overall, we provide evidence that LPS-mediated activation of macrophages suppresses lipolysis via induction of HILPDA, thereby reducing the availability of proinflammatory lipid precursors and suppressing the production of PGE2 and IL-6.

The tumor microenvironment is highly complex, and immune escape is currently considered an important hallmark of cancer, largely contributing to tumor progression and metastasis. Named for their capability of killing target cells autonomously, natural killer (NK) cells serve as the main effector cells toward cancer in innate immunity and are highly heterogeneous in the microenvironment. Most current treatment options harnessing the tumor microenvironment focus on T cell-immunity, either by promoting activating signals or suppressing inhibitory ones. The limited success achieved by T cell immunotherapy highlights the importance of developing new-generation immunotherapeutics, for example utilizing previously ignored NK cells. Although tumors also evolve to resist NK cell-induced cytotoxicity, cytokine supplement, blockade of suppressive molecules and genetic engineering of NK cells may overcome such resistance with great promise in both solid and hematological malignancies. In this review, we summarized the fundamental characteristics and recent advances of NK cells within tumor immunometabolic microenvironment, and discussed potential application and limitations of emerging NK cell-based therapeutic strategies in the era of presicion medicine.

[This corrects the article DOI: 10.3389/fimmu.2023.1276357.].

The most prevalent diseases of our time, non-communicable diseases (NCDs) (including obesity, type 2 diabetes, cardiovascular diseases and some types of cancer) are rising worldwide. All of them share the condition of an “inflammatory disorder”, with impaired immune functions frequently caused or accompanied by alterations in gut microbiota. These multifactorial maladies also have in common malnutrition related to physiopathology. In this context, diet is the greatest modulator of immune system–microbiota crosstalk, and much interest, and new challenges, are arising in the area of precision nutrition as a way towards treatment and prevention. It is a fact that the westernized diet (WD) is partly responsible for the increased prevalence of NCDs, negatively affecting both gut microbiota and the immune system. Conversely, other nutritional approaches, such as Mediterranean diet (MD), positively influence immune system and gut microbiota, and is proposed not only as a potential tool in the clinical management of different disease conditions, but also for prevention and health promotion globally. Thus, the purpose of this review is to determine the regulatory role of nutritional components of WD and MD in the gut microbiota and immune system interplay, in order to understand, and create awareness of, the influence of diet over both key components.

Traditionally cellular respiration or metabolism has been viewed as catabolic and anabolic pathways generating energy and biosynthetic precursors required for growth and general cellular maintenance. However, growing literature provides evidence of a much broader role for metabolic reactions and processes in controlling immunological effector functions. Much of this research into immunometabolism has focused on macrophages, cells that are central in pro- as well as anti-inflammatory responses-responses that in turn are a direct result of metabolic reprogramming. As we learn more about the precise role of metabolic pathways and pathway intermediates in immune function, a novel opportunity to target immunometabolism therapeutically has emerged. Here, we review the current understanding of the regulation of macrophage function through metabolic remodeling.