The tumor-immune microenvironment (TIME) plays a critical role in tumor development and metastasis, as it influences the evolution of tumor cells and fosters an immunosuppressive state by intervening the metabolic reprogramming of infiltrating immune cells. Aging and diet significantly impact the metabolic reprogramming of the TIME, contributing to cancer progression and immune evasion. With aging, immune cell function declines, leading to a proinflammatory state and metabolic alterations such as increased oxidative stress and mitochondrial dysfunction, which compromise antitumor immunity. Similarly, dietary factors, particularly high-fat and high-sugar diets, promote metabolic shifts, creating a permissive TIME by fostering tumor-supportive immune cell phenotypes while impairing the tumoricidal activity of immune cells. In contrast, dietary restrictions have been shown to restore immune function by modulating metabolism and enhancing antitumor immune responses. Here, we discuss the intricate interplay between aging, diet, and metabolic reprogramming in shaping the TIME, with a particular focus on T cells, and highlight therapeutic strategies targeting these pathways to empower antitumor immunity.

A growing part of the human population is affected by circadian misalignment caused by deregulated sleep, increased nighttime light exposure and erratic eating patterns. Thus, circadian rhythms are a key research area, with compelling links to cancer. Here, we review the circadian regulation of critical cellular processes, including immunity, metabolism, cell cycle control and DNA repair, under physiological homeostasis and in cancer. We discuss the divergent evidence indicating tissue-specific roles of the circadian clock in different cancer types and the potential link between circadian misalignment and early-onset cancers. Finally, we outline how understanding the circadian clock can improve cancer prevention and chronomedicine-based therapies.

To explore the role of genes related to fatty acid metabolism in lung adenocarcinoma classification and prognosis.

Transcriptome and clinical data from the TCGA database and GEO database were collected, the expression of prognostic fatty acid metabolism-related genes in LUAD patients was analyzed, and key genes related to both fatty acid metabolism and subtype were identified. These key genes were further filtered via the LASSO regression method, and the retained genes were used to construct a risk-scoring model. The biological function of RPS4Y1 was verified by cell viability, colony formation, migration, and flow cytometry assays. Finally, immune infiltration and drug sensitivity were analyzed in the high- and low-risk groups.

31 key FAMGs associated with prognosis were identified in LUAD patients. LUAD cases were divided into 3 subtypes on the basis of the expression of these genes. The DEGs between the different subtypes were associated mainly with amino acid metabolic pathways. In addition, among the 46 DEGs between subtypes, 5 key FAMGs (SCGB3 A2, PGC, ADH7, RPS4Y1, and KRT6 A) were identified as the best prognostic markers via LASSO regression to establish a risk scoring model. Patients with low risk scores had a better prognosis and a greater degree of immune cell infiltration than those with high risk scores. RPS4Y1 is highly expressed in LUAD, and its knockdown significantly inhibits the growth of tumor cells. Moreover, we also analyzed drugs likely to be effective for the high- and low-risk groups.

FAMGs play important roles in LUAD, and the key genes identified may be new targets for LUAD treatment.

Natural killer (NK) cells are innate lymphocytes that are crucial for eliminating malignant and infected cells, and have significant therapeutic potential against cancer and viral infections. However, their functionality is often impaired under pathological conditions. Emerging evidence identifies mitochondria as key regulators of NK cell metabolism, fitness, and fate. This review examines how mitochondrial dysfunction impacts on NK cell activity in cancer, viral infections, and inflammatory disorders. We discuss strategies to target mitochondrial architecture, dynamics, and function as potential therapies to restore NK cell fitness. Finally, we highlight unanswered questions and future directions to better understand mitochondrial regulation in NK cells and its implications for therapeutic development.

Natural killer (NK) cells are innate immune cells able to recognize and eliminate virus-infected cells. NK cell activity strongly correlates with a metabolic reprogramming and breakdown of fatty acids by β-oxidation during virus infections. However, there is limited knowledge regarding the impact of obesity on antiviral NK cell functions. Here, employing the Friend retrovirus mouse model, we show that the cytotoxicity and cytokine production of NK cells was impaired in obesity, leading to higher viral loads. NK cells suppression in obesity was mediated by activated Tregs. Furthermore, obese mice that were switched back to a regular diet showed complete recovery of the NK cell activity. Interestingly, feeding mice with a high-fat diet (HFD) for just ten days caused NK cell dysfunction and increased retroviral burden. This study is the first to link the detrimental impact of an obesity-induced immunosuppressive microenvironment with NK cell dysfunction during an acute retroviral infection.

Leptin, an adipokine related to obesity, is mainly known for its role in regulating energy homeostasis and appetite by working via the leptin receptor. Recently, different groups have demonstrated that apart from adipocytes, specific cell types associated with cancer and tumor microenvironments express leptin and leptin receptors. This tumor microenvironment-associated leptin-leptin receptor signaling contributes to the different hallmarks of cancer, ranging from inflammatory changes to metastasis. Eventually, it has also been reported that high serum level of leptin, a characteristic of obese people, is linked to enhanced tumor growth. On the other hand, leptin can influence both innate as well as adaptive immunity related to cancer. Overall, leptin's role in modulating cancer is controversial. So, in this review, we summarized the role of leptin in shaping different forms of cancer that are influenced by leptin-leptin receptor signaling with special emphasis on immunomodulation and inflammatory events and also discussed the possible therapeutic interventions to date. As this review work, with the collection of different updated knowledge, has summarized the role of leptin on cancer, it would be useful material to have on hand for both beginners as well as pioneers of these and related fields.

High-grade serous ovarian cancer (HGSOC) remains an urgent unmet clinical need, with more than 70% of patients presenting with metastatic disease. Many patients develop large volumes of ascites, which promotes metastasis and is associated with poor therapeutic response and survival. Immunotherapy trials have shown limited success, highlighting the need to better understand HGSOC immunology. Here, we analyzed cytotoxic lymphocytes [natural killer (NK), T, and innate T cells] from patients with HGSOC and observed widespread dysfunction across primary and metastatic sites. Although nutrient rich, ascites was immunosuppressive for all lymphocyte subsets. NK cell dysfunction was driven by uptake of polar lipids, with associated dysregulation in lipid storage. Phosphatidylcholine was a key immunosuppressive metabolite, disrupting NK cell membrane order and cytotoxicity. Blocking lipid uptake through SR-B1 protected NK cell antitumor functions in ascites. These findings offer insights into immune suppression in HGSOC and have important implications for the design of future immunotherapies.

Extending healthspan - the years lived in optimal health - holds transformative potential to reduce chronic diseases and healthcare costs. Dietary restriction (DR), particularly when combined with nutrient-rich diets and exercise, is among the most effective, evidence-based strategies for enhancing metabolic health and longevity. By targeting fundamental pathways, it mitigates the onset and progression of obesity, type 2 diabetes (T2D), cardiovascular disease (CVD), neurodegeneration, and cancer. This review synthesizes human data on the impact of DR and exercise on metabolic and age-related diseases, while emphasizing key biological mechanisms such as nutrient sensing, insulin sensitivity, inflammation, mitochondrial function, and gut microbiota. We also examine the emerging role of pharmacologically induced DR, focusing on glucagon-like peptide 1 (GLP-1) receptor agonists (RAs) that partially mimic DR and present opportunities for chronic disease prevention.

Obesity is a condition of excess body fat. Although it has been identified as a risk factor for multiple cancers in part because of its 'metainflammatory' state, it has also been paradoxically associated with improved response to immune checkpoint inhibition. To study obesity, one must first understand how best to define it. In this opinion article, we briefly discuss factors that are impacting net effects of obesity and highlight complementary measures that should be considered beyond body mass index (BMI) when attempting to assess the potential effects of obesity in cancer.

White adipose tissue (WAT) is crucial for whole-body energy homeostasis and plays an important role in metabolic and hormonal regulation. While healthy WAT undergoes controlled expansion and contraction to meet the body's requirements, dysfunctional WAT in conditions like obesity is characterized by excessive tissue expansion, alterations in lipid homeostasis, inflammation, hypoxia, and fibrosis. Obesity is strongly associated with an increased risk of numerous cancers, with obesity-induced WAT dysfunction influencing cancer development through various mechanisms involving both systemic and local interactions between adipose tissue and tumors. Unhealthy obese WAT affects circulating levels of free fatty acids and factors like leptin, adiponectin, and insulin, altering systemic lipid metabolism and inducing inflammation that supports tumor growth. Similar mechanisms are observed locally in an adipose-rich tumor microenvironment (TME), where WAT cells can also trigger extracellular matrix remodeling, thereby enhancing the TME's ability to promote tumor growth. Moreover, tumors reciprocally interact with WAT, creating a bidirectional communication that further enhances tumorigenesis. This review focuses on the complex interplay between obesity, WAT dysfunction, and primary tumor growth, highlighting potential targets for therapeutic intervention.

In recent years, the incidence and mortality of pancreatic cancer (PC) are increasing year by year. The highly heterogeneous nature of PC, its strong immune escape ability and easy metastasis make it the most lethal malignant tumor in the world. With the rapid development of sequencing technology, the complex components in the tumor microenvironment (TME) of PC have been gradually revealed. Interactions between pancreatic stellate cells, tumor-associated fibroblasts, various types of immune cells, and cancer cells collectively promote metabolic reprogramming of all types of cells. This metabolic reprogramming further enhances the immune escape mechanism of tumor cells and ultimately induces tumor cells to become severely resistant to chemotherapy and immunotherapy. On the one hand, PC cells achieve re and rational utilization of glucose, amino acids and lipids through metabolic reprogramming, which in turn accomplishes biosynthesis and energy metabolism requirements. Under such conditions, tumorigenesis, proliferation and metastasis are ultimately promoted. On the other hand, various types of immune cells in the tumor immune microenvironment (TIME) also undergo metabolic reprogramming, which leads to tumor progression and suppression of anti-immune responses by inhibiting the function of normal anti-tumor immune cells and enhancing the function of immunosuppressive cells. The aim of this review is to explore the interaction between the immune microenvironment and metabolic reprogramming in PC. The focus is to summarize the specific mechanisms of action of metabolic reprogramming of PC cells and metabolic reprogramming of immune cells. In addition, this review will summarize the mechanisms of immunotherapy resistance in PC cells. In the future, targeting specific mechanisms of metabolic reprogramming will provide a solid theoretical basis for the development of combination therapies for PC.

Circadian rhythms send messages to regulate the sleep-wake cycle in living beings, which, regulate various biological activities. It is well known that altered sleep-wake cycles affect host metabolism and significantly deregulate the host immunity. The dysregulation of circadian-related genes is critical for various malignancies. One of the hallmarks of cancer is altered metabolism, the effects of which spill into surrounding microenvironments. Here, we review the emerging literature linking the circadian immunometabolic axis to cancer. Small metabolites are the products of various metabolic pathways, that are usually perturbed in cancer. Genes that regulate circadian rhythms also regulate host metabolism and control metabolite content in the tumor microenvironment. Immune cell infiltration into the tumor site is critical to perform anticancer functions, and altered metabolite content affects their trafficking to the tumor site. A compromised immune response in the tumor microenvironment aids cancer cell proliferation and immune evasion, resulting in metastases. The role of circadian rhythms in these processes is largely overlooked and demands renewed attention in the search for targets against cancer growth and spread. The precision medicine approach requires targeting the circadian immune metabolism in cancer.

Obesity increases the risk of papillary thyroid carcinoma (PTC) and lymph node metastasis (LNM), possibly via modulation of the tumor immunological microenvironment.

The STROCSS guideline was followed to conduct a retrospective cohort study. Binary logistic regression analysis with odds ratios (OR) was performed to assess the association between tumor-infiltrating lymphocytes (TILs), obesity, and LNM. Using The Cancer Genome Atlas (TCGA) data, we examined the relationship between immune cell subsets and obesity-regulating molecules in thyroid cancer tissues. The Cox regression risk model was used to analyze the prognosis of thyroid cancer.

After adjusting for confounding factors, our findings revealed that overweight and obesity were associated with a decrease in TIL infiltration (OR 0.876, p = 0.005 and OR 0.795, p = 0.001, respectively). Furthermore, these conditions were observed to be correlated with increased likelihood of LNM (OR 1.134, p = 0.005 and OR 1.307, p < 0.001, respectively). On the contrary, TIL infiltration was inversely associated with LNM (OR 0.868, p < 0.001). When controlling for TIL infiltration as the sole variable, the combination of obesity and TIL infiltration did not independently predict LNM (adjusted OR 1.442, p = 0.113). However, obesity alone was found to elevate the likelihood of LNM (adjusted OR 1.539, p = 0.02). Additionally, adiponectin (a crucial adipokine) was reduced in obesity and demonstrated a negative correlation with the abundance of infiltrated dendritic cells and regulatory T cells, as evidenced by TCGA data analysis. Furthermore, ADIPOR2 expression negatively correlated with LNM and positively associated with unfavorable prognosis in PTC, with a hazard ratio of 0.480 (p = 0.007).

TIL infiltration may affect obesity-associated PTC LNM. Obesity may affect LNM and result in poor prognosis through ADIPOR2 regulation of antitumor immune cells.

Metabolic reprogramming of cancer cells and the tumour microenvironment are pivotal characteristics of cancers, and studying these processes offer insights and avenues for cancer diagnostics and therapeutics. Recent advancements have underscored the impact of host systemic features, termed macroenvironment, on facilitating cancer progression. During tumorigenesis, these inherent features of the host, such as germline genetics, immune profile and the metabolic status, influence how the body responds to cancer. In parallel, as cancer grows, it induces systemic effects beyond the primary tumour site and affects the macroenvironment, for example, through inflammation, the metabolic end-stage syndrome of cachexia, and metabolic dysregulation. Therefore, understanding the intricate metabolic interplay between the tumour and the host is a growing frontier in advancing cancer diagnosis and therapy. In this Review, we explore the specific contribution of the metabolic fitness of the host to cancer initiation, progression and response to therapy. We then delineate the complex metabolic crosstalk between the tumour, the microenvironment and the host, which promotes disease progression to metastasis and cachexia. The metabolic relationships among the host, cancer pathogenesis and the consequent responsive systemic manifestations during cancer progression provide new perspectives for mechanistic cancer therapy and improved management of patients with cancer.

Aberrant lipid metabolism is a well-recognized hallmark of cancer. Notably, breast cancer (BC) arises from a lipid-rich microenvironment and depends significantly on lipid metabolic reprogramming to fulfill its developmental requirements. In this review, we revisit the pivotal role of lipid metabolism in BC, underscoring its impact on the progression and tumor microenvironment. Firstly, we delineate the overall landscape of lipid metabolism in BC, highlighting its roles in tumor progression and patient prognosis. Given that lipids can also act as signaling molecules, we next describe the lipid signaling exchanges between BC cells and other cellular components in the tumor microenvironment. Additionally, we summarize the therapeutic potential of targeting lipid metabolism from the aspects of lipid metabolism processes, lipid-related transcription factors and immunotherapy in BC. Finally, we discuss the possibilities and problems associated with clinical applications of lipid‑targeted therapy in BC, and propose new research directions with advances in spatiotemporal multi-omics.

Lipid metabolism reprogram plays key roles in breast cancer tumorigenesis and immune escape. The underlying mechanism and potential regulator were barely investigated. We thus established an in vivo tumorigenesis model, mice-bearing breast cancer cells were treated with an ordinary diet and high-fat diet, species were collected and subjected to circRNA sequence to scan the potential circRNAs regulating the lipid metabolism. CircSpdyA was one of the most upregulated circRNAs and had the potential to encode a 127-aa micro peptide (referred to as 127aa). 127 aa promotes tumorigenesis through promoting the fatty acid de novo synthesis by directly binding to FASN. Single-cell sequence indicated 127aa inhibited NK cell infiltration and function. This was achieved by inhibiting the transcription of NK cell activators epigenetically. Moreover, lipid-laden from 127aa positive cancer cells transferred to NK cells inhibited the cytotoxicity. Taken together, circSpdyA encoded 127aa promotes fatty acid de novo synthesis through directly binding with FASN and induced NK cell repression by inhibiting the transcription of NK cell activators.

The importance of metabolic pathways in regulating immune responses is now well established, and a mapping of the bioenergetic metabolism of different immune cell types is under way. CD8 T cells and natural killer (NK) cells contribute to cancer immunosurveillance through their cytotoxic functions and secretion of cytokines and chemokines, complementing each other in target recognition mechanisms. Several immunotherapies leverage these cell types by either stimulating their activity or redirecting their specificity against tumour cells. However, the anticancer activity of CD8 T cells and NK cells is rapidly diminished in the tumour microenvironment, closely linked to a decline in their metabolic capacities. Various strategies have been developed to restore cancer immunosurveillance, including targeting bioenergetic metabolism or genetic engineering. This Review provides an overview of metabolic dysfunction in CD8 T cells and NK cells within the tumour microenvironment, highlighting current therapies aiming to overcome these issues.

Dyslipidemia is a common metabolic disorder around the world, with a higher incidence in the population of childbearing age and those experiencing infertility. Increasing research has been focused on the impact of dyslipidemia on female reproduction. This article reviews relevant clinical and basic science research on the effects of dyslipidemia on female reproduction, particularly paying attention to immune inflammatory changes in the endometrium. A comprehensive overview of the physiological effects of lipid metabolism on innate and adaptive immunity is provided, specifically examining the relationship between lipid metabolism and endometrial immune homeostasis, as well as the changes observed in women with reproductive failures. Moreover, the alterations in endometrial gene expressions and immune effectors in women with dyslipidemia and reproductive disorders are discussed, offering a new perspective on the reproductive disorders in women with dyslipidemia. Considering the significant involvement of lipid metabolism in human reproduction, gaining a deeper insight into dyslipidemia and female reproduction could have important clinical implications for the diagnosis and management of female reproductive disorders.

Obesity is a chronic inflammatory disease that affects more than 1 billion people worldwide and is associated with various metabolic and physiological dysfunctions, directly impacting the dynamics of the immune response, partly due to elevated leptin levels. Leptin is an important peptide hormone that regulates neuroendocrine function and energy homeostasis, with its blood levels reflecting energy reserves, fat mass, or energy deprivation. This hormone also plays a fundamental role in regulating immune function, including the activity of NK cells, which are essential components in antiviral and antitumor activity. In obese individuals, leptin resistance is commonly established, however, NK cells and other immune components remain responsive to this hormone. So far, leptin has demonstrated paradoxical activities of these cells, often associated with a dysfunctional profile when associated with obesity. The excessive fat is usually related to metabolic remodeling in NK cells, resulting in compromised antitumor responses due to reduced cytotoxic capacity and decreased expression of cytokines important for these defense mechanisms, such as IFN-γ. Therefore, this review approaches a better understanding of the immunoendocrine interactions between leptin and NK cells in the context of obesity.

Over the past two decades, the "hallmarks of cancer" have revolutionized cancer research and highlighted the crucial roles of inflammation and immunity. Protumorigenic inflammation promotes cancer development along with inhibition of antitumor immunity, shaping the tumor microenvironment (TME) toward a tumor-permissive state and further enhancing the malignant potential of cancer cells. This immunosuppressive TME allows tumors to evade immunosurveillance. Thus, understanding the complex interplay between tumors and the immune system within the TME has become pivotal, especially with the advent of immunotherapy. Although immunotherapy has achieved notable success in many malignancies, primary liver cancer, particularly hepatocellular carcinoma, presents unique challenges. The hepatic immunosuppressive environment poses obstacles to the effectiveness of immunotherapy, along with high mortality rates and limited treatment options for patients with liver cancer. In this review, we discuss current understanding of the complex immune-mediated mechanisms underlying liver neoplasms, focusing on hepatocellular carcinoma and liver metastases. We describe the molecular and cellular heterogeneity within the TME, highlighting how this presents unique challenges and opportunities for immunotherapy in liver cancers. By unraveling the immune landscape of liver neoplasms, this review aims to contribute to the development of more effective therapeutic interventions, ultimately improving clinical outcomes for patients with liver cancer.

Tumor metabolism is crucial in the continuous advancement and complex growth of cancer. The emerging field of nanotechnology has made significant strides in enhancing the understanding of the complex metabolic intricacies inherent to tumors, offering potential avenues for their strategic manipulation to achieve therapeutic goals. This comprehensive review delves into the interplay between tumor metabolism and various facets of cancer, encompassing its origins, progression, and the formidable challenges posed by metastasis. Simultaneously, it underscores the classification of programmable nanomodulators and their transformative impact on enhancing cancer treatment, particularly when integrated with modalities such as chemotherapy, radiotherapy, and immunotherapy. This review also encapsulates the mechanisms by which nanomodulators modulate tumor metabolism, including the delivery of metabolic inhibitors, regulation of oxidative stress, pH value modulation, nanoenzyme catalysis, nutrient deprivation, and RNA interference technology, among others. Additionally, the review delves into the prospects and challenges of nanomodulators in clinical applications. Finally, the innovative concept of using nanomodulators to reprogram metabolic pathways is introduced, aiming to transform cancer cells back into normal cells. This review underscores the profound impact that tailored nanomodulators can have on tumor metabolic, charting a path toward pioneering precision therapies for cancer.

Recent advances have highlighted the crucial role of metabolic reprogramming in shaping the functions of innate lymphoid cells (ILCs), which are vital for tissue immunity and homeostasis. As tissue-resident cells, ILCs dynamically respond to local environmental cues, with tissue-derived metabolites such as short-chain fatty acids and amino acids directly modulating their effector functions. The metabolic states of ILC subsets-ILC1, ILC2, and ILC3-are closely linked to their ability to produce cytokines, sustain survival, and drive proliferation. This review provides a comprehensive analysis of how key metabolic pathways, including glycolysis, oxidative phosphorylation, and fatty acid oxidation, influence ILC activation and function. Furthermore, we explore the complex interactions between these metabolic pathways and tissue-specific metabolites, which can shape ILC-mediated immune responses in health and disease. Understanding these interactions reveals new insights into the pathogenesis of conditions such as asthma, inflammatory bowel disease, and cancer. A deeper understanding of these mechanisms may not only advance our knowledge of disease pathogenesis but also lead to the development of novel therapeutic strategies targeting metabolic pathways in ILCs to treat tissue-specific immune disorders.

Innate training of macrophages can be beneficial for the clearance of pathogens. However, for certain chronic conditions, innate training can have detrimental effects due to an excessive production of pro-inflammatory cytokines. Obesity is a condition that is associated with a range of increased pro-inflammatory training stimuli including the free fatty acid palmitate. Mesenchymal stromal cells (MSCs) are powerful immunomodulators and known to suppress inflammatory macrophages via a range of soluble factors. We show that palmitate training of murine bone-marrow-derived macrophages and human monocyte-derived macrophages (MDMs) results in an increased production of TNFα and IL-6 upon stimulation with lipopolysaccharide and is associated with epigenetic remodeling. Palmitate training led to metabolic changes, however, MSCs did not alter the metabolic profile of human MDMs. Using a transwell system, we demonstrated that human bone marrow MSCs block palmitate training in both murine and human macrophages suggesting the involvement of secreted factors. MSC disruption of the training process occurs through more than one pathway. Suppression of palmitate-enhanced TNFα production is associated with cyclooxygenase-2 activity in MSCs, while secretion of interleukin-1 receptor antagonist by MSCs is required to suppress palmitate-enhanced IL-6 production in MDMs.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor outcomes due to frequent recurrence, metastasis, and resistance to treatment. A major contributor to this resistance is the tumor's ability to suppress natural killer (NK) cells, which are key players in the immune system's fight against cancer. In PDAC, the tumor microenvironment (TME) creates conditions that impair NK cell function, including reduced proliferation, weakened cytotoxicity, and limited tumor infiltration. This review examines how interactions between tumor-derived factors, NK cells, and the TME contribute to tumor progression and treatment resistance. To address these challenges, we propose a new "Triple NK Cell Biomarker Approach". This strategy focuses on identifying biomarkers from three critical areas: tumor characteristics, TME factors, and NK cell suppression mechanisms. This approach could guide personalized treatments to enhance NK cell activity. Additionally, we highlight the potential of combining NK cell-based therapies with conventional treatments and repurposed drugs to improve outcomes for PDAC patients. While progress has been made, more research is needed to better understand NK cell dysfunction and develop effective therapies to overcome these barriers.

Lung cancer is a frequent malignancy with a poor prognosis. Extensive metabolic alterations are involved in carcinogenesis and could, therefore, serve as a reliable prognostic phenotype.

Our study aimed to develop a prognosis signature and explore the relationship between metabolic characteristic-related signature and immune infiltration in lung adenocarcinoma (LUAD).

TCGA-LUAD and GSE31210 datasets were used as a training set and a validation set, respectively.

A total of 513 LUAD samples collected from The Cancer Genome Atlas database (TCGA-LUAD) were used as a training dataset. Molecular subtypes were classified by consensus clustering, and prognostic genes related to metabolism were analyzed based on Differentially Expressed Genes (DEGs), Protein-Protein Interaction (PPI) network, the univariate/multivariate- and Lasso- Cox regression analysis.

Two molecular subtypes with significant survival differences were divided by the metabolism gene sets. The DEGs between the two subtypes were identified by integrated analysis and then used to develop an 8-gene signature (TTK, TOP2A, KIF15, DLGAP5, PLK1, PTTG1, ECT2, and ANLN) for predicting LUAD prognosis. Overexpression of the 8 genes was significantly correlated with worse prognostic outcomes. RiskScore was an independent factor that could divide LUAD patients into low- and high-risk groups. Specifically, high-risk patients had poorer prognoses and higher immune escape. The Receiver Operating Characteristic (ROC) curve showed strong performance of the RiskScore model in estimating 1-, 3- and 5-year survival in both training and validation sets. Finally, an optimized nomogram model was developed and contributed the most to the prognostic prediction in LUAD.

The current model could help effectively identify high-risk patients and suggest the most effective drug and treatment candidates for patients with LUAD.

A slew of common metabolic disorders, including type 2 diabetes, metabolic dysfunction-associated steatotic liver disease and steatohepatitis, are exponentially increasing in our sedentary and overfed society. While macronutrients directly impact metabolism and bioenergetics, new evidence implicates immune cells as critical sensors of nutritional cues and important regulators of metabolic homeostasis. A deeper interrogation of the intricate and multipartite interactions between dietary components, immune cells and metabolically active tissues is needed for a better understanding of metabolic regulation and development of new treatments for common metabolic diseases. Responding to macronutrients and micronutrients, immune cells play pivotal roles in interorgan communication between the microbiota, small intestine, metabolically active cells including hepatocytes and adipocytes, and the brain, which controls feeding behavior and energy expenditure. This Review focuses on the response of myeloid cells and innate lymphocytes to dietary cues, their cross-regulatory interactions and roles in normal and aberrant metabolic control.

The immune system plays fundamental roles in maintaining physiological homeostasis. With the increasing prevalence of obesity-a state characterized by chronic inflammation and systemic dyshomeostasis-there is growing scientific and clinical interest in understanding how obesity reshapes immune function. In this review, we propose that obesity is not merely an altered metabolic state but also a fundamentally altered immunological state. We summarize key seminal and recent findings that elucidate how obesity influences immune function, spanning its classical role in microbial defense, its contribution to maladaptive inflammatory diseases such as asthma, and its impact on antitumor immunity. We also explore how obesity modulates immune function within tissue parenchyma, with a particular focus on the role of T cells in adipose tissue. Finally, we consider areas for future research, including investigation of the durable aspects of obesity on immunological function even after weight loss, such as those observed with glucagon-like peptide-1 (GLP-1) receptor agonist treatment. Altogether, this review emphasizes the critical role of systemic metabolism in shaping immune cell functions, with profound implications for tissue homeostasis across various physiological contexts.

Lipids are metabolic messengers essential for energy production, membrane structure, and signal transduction. Beyond their recognized role, lipids have emerged as metabolic rheostats of T cell responses, with distinct species differentially modulating CD8+ T cell (CTL) fate and function. Indeed, lipids can influence T cell signaling by altering their membrane composition; in addition, they can affect the differentiation path of T cells through cellular metabolism. This Review discusses the ability of lipids to shape T cell phenotypes and functions. Based on this link between lipid metabolism, metabolic fitness and immunosurveillance, we suggest that lipid could be rationally integrated in the context of immunotherapies to fine-tune fitness and function of adoptive T cell therapy (ACT) products.

African American (AA) women are disproportionately affected by obesity and hyperlipidemia, particularly in the setting of adverse social determinants of health (aSDoH) that contribute to health disparities. Obesity, hyperlipidemia, and aSDoH appear to impair NK cells. As potential common underlying mechanisms are largely unknown, we sought to investigate common signaling pathways involved in NK cell dysfunction related to obesity and hyperlipidemia in AA women from underresourced neighborhoods. We determined in freshly isolated NK cells that obesity and measures of aSDoH were associated with a shift in NK cell subsets away from CD56dim/CD16+ cytotoxic NK cells. Using ex vivo data, we identified LDL as a marker related to NK cell function in an AA population from underresourced neighborhoods. Additionally, NK cells from AA women with obesity and LDL-treated NK cells displayed a loss in NK cell function. Comparative unbiased RNA-sequencing analysis revealed DUSP1 as a common factor. Subsequently, chemical inhibition of Dusp1 and Dusp1 overexpression in NK cells highlighted its significance in NK cell function and lysosome biogenesis in a mTOR/TFEB-related fashion. Our data demonstrate a pathway by which obesity and hyperlipidemia in the setting of aSDoH may relate to NK cell dysfunction, making DUSP1 an important target for further investigation of health disparities.

Ferroptosis, a novel form of cell death discovered in recent years, is typically accompanied by significant iron accumulation and lipid peroxidation during the process. This article systematically elucidates how tumor metabolic reprogramming affects the ferroptosis process in tumor cells. The paper outlines the basic concepts and physiological significance of tumor metabolic reprogramming and ferroptosis, and delves into the specific regulatory mechanisms of glucose metabolism, protein metabolism, and lipid metabolism on ferroptosis. We also explore how complex metabolic changes in the tumor microenvironment further influence the response of tumor cells to ferroptosis. Glucose metabolism modulates ferroptosis sensitivity by influencing intracellular energetic status and redox balance; protein metabolism, involving amino acid metabolism and protein synthesis, plays a crucial role in the initiation and progression of ferroptosis; and the relationship between lipid metabolism and ferroptosis primarily manifests in the generation and elimination of lipid peroxides. This review aims to provide a new perspective on how tumor cells regulate ferroptosis through metabolic reprogramming, with the ultimate goal of offering a theoretical basis for developing novel therapeutic strategies targeting tumor metabolism and ferroptosis.

Rationale Obesity is an independent risk factor for the occurrence and development of tumors. Obesity is influenced by signaling of adipokines, which are secreted factors from adipocytes and resident immune cells within adipose tissues that mediate lipid metabolism. More recently, adipokines have been implicated in chronic inflammation as well as in tumor formation and growth. Among them, resistin has received increasing attention in research related to the growth and expansion of solid tumors and hematological cancers through various signaling pathways. Objective and findings We reviewed the physiological, biochemical, and immune functions of adipose tissue, with a focus on the structure and expression of resistin and adipokines within multiple adipose cell types, their signaling pathways and putative effects on tumor cells, as well as their in vivo regulation. Current evidence indicates that adipokines such as resistin act as pro-inflammatory factors to stimulate immune cells which, in turn, promotes tumor angiogenesis, connective tissue proliferation, and matrix fibrosis. Concurrently, in states of metabolic dysfunction and lipotoxicity in obese individuals, the numbers and functions of immune cells are compromised, leading to an immunosuppressive environment that fosters tumor cell survival and weak cancer immune monitoring. Conclusion Adipokines such as resistin are important to the development of obesity-related tumors. Clarifying the roles for obesity-related factors in immune regulation and tumor progression may lead to the discovery of novel anti-tumor strategies for targeting obesity factors such as resistin to limit tumor growth and manage obesity, or both.

Diet and exercise are modifiable lifestyle factors known to have a major influence on metabolism. Clinical practice addresses diseases of altered metabolism such as diabetes or hypertension by altering these factors. Despite enormous public interest, there are limited defined diet and exercise regimens for cancer patients. Nevertheless, the molecular basis of cancer has converged over the past 15 years on an essential role for altered metabolism in cancer. However, our understanding of the molecular mechanisms that underlie the impact of diet and exercise on cancer metabolism is in its very early stages. In this work, we propose conceptual frameworks for understanding the consequences of diet and exercise on cancer cell metabolism and tumor biology and also highlight recent developments. By advancing our mechanistic understanding, we also discuss actionable ways that such interventions could eventually reach the mainstay of both medical oncology and cancer control and prevention.

Subcutaneous adipose tissue (SAT) is the deepest component of the three-layered cutaneous integument. While mesenteric adipose tissue-based immune processes have gained recognition in the context of the metabolic syndrome, SAT has been traditionally considered primarily for energy storage, with less attention to its immune functions. SAT harbors a reservoir of immune and stromal cells that significantly impact metabolic and immunologic processes not only in the skin, but even on a systemic level. These processes include wound healing, cutaneous and systemic infections, immunometabolic, and autoimmune diseases, inflammatory skin diseases, as well as neoplastic conditions. A better understanding of SAT immune functions in different processes, could open avenues for novel therapeutic interventions. Targeting SAT may not only address SAT-specific diseases but also offer potential treatments for cutaneous or even systemic conditions. This review aims to provide a comprehensive overview on SAT's structure and functions, highlight recent advancements in understanding its role in both homeostatic and pathological conditions within and beyond the skin, and discuss the main questions for future research in the field.

Mitochondria play a central role in cellular energy production and metabolic regulation, and their function has been identified as a key factor influencing tumor immune responses. This review provides a comprehensive overview of the latest advancements in understanding the role of mitochondria in tumor immune surveillance, covering both innate and adaptive immune responses. Specifically, it outlines how mitochondria influence the function of the tumor immune system, underscoring their crucial role in modulating immune cell behavior to either promote or inhibit tumor development and progression. Additionally, this review highlights emerging drug interventions targeting mitochondria, including novel small molecules with significant potential in cancer therapy. Through an in-depth analysis, it explores how these innovative strategies could improve the efficacy and outlook of tumor treatment.

To explore the role of radiomics in predicting the prognosis of proximal esophageal cancer and to investigate the biological underpinning of radiomics in identifying different prognoses.

A total of 170 patients with pathologically and endoscopically confirmed proximal esophageal cancer from two centers were enrolled. Radiomics models were established by five machine learning approaches. The optimal radiomics model was selected using receiver operating curve analysis. Bioinformatics methods were applied to explore the potential biological mechanisms. Nomograms based on radiomics and clinical-radiomics features were constructed and assessed by receiver operating characteristics, calibration, and decision curve analyses net reclassification improvement, and integrated discrimination improvement evaluations.

The peritumoral models performed well with the majority of classifiers in the training and validation sets, with the dual-region radiomics model showing the highest integrated area under the curve values of 0.9763 and 0.9471, respectively, and outperforming the single-region models. The clinical-radiomics nomogram showed better predictive performance than the clinical nomogram, with a net reclassification improvement of 34.4% (p = 0.02) and integrated discrimination improvement of 10% (p = 0.007). Gene ontology enrichment analysis revealed that lipid metabolism-related functions are potentially crucial in the process by which the radiomics score could stratify patients.

A combination of peritumoral radiomics features could improve the predictive performance of intratumoral radiomics to estimate overall survival after definitive chemoradiotherapy in patients with proximal esophageal cancer. Radiomics features could provide insights into the lipid metabolism associated with radioresistance and hold great potential to guide personalized care.

This study demonstrates that incorporating peritumoral radiomics features enhances the predictive accuracy of overall survival in proximal esophageal cancer patients after chemoradiotherapy, and suggests a link between radiomics and lipid metabolism in radioresistance, highlighting its potential for personalized treatment strategies.

Peritumoral region radiomics features could predict the prognosis of proximal esophageal cancer. Dual-region radiomics features showed significantly better predictive performance. Radiomics features can provide insights into the lipid metabolism associated with radioresistance.

A poor maternal diet during pregnancy predisposes the infant to severe lower respiratory tract infections (sLRIs), which, in turn, increases childhood asthma risk; however, the underlying mechanisms remain poorly understood. Here, we show that the offspring of high-fat diet (HFD)-fed mothers (HFD-reared pups) developed an sLRI following pneumovirus inoculation in early life and subsequent asthma in later life upon allergen exposure. Prior to infection, HFD-reared pups developed microbial dysbiosis and low-grade systemic inflammation (LGSI), characterized by hyperneutropoiesis in the liver and elevated inflammatory cytokine expression, most notably granulocyte-colony stimulating factor (G-CSF), interleukin-17A (IL-17A), IL-6 and soluble IL-6 receptor (sIL-6R) (indicative of IL-6 trans-signaling) in the circulation and multiple organs but most prominently the liver. Inhibition of IL-6 trans-signaling using sgp130Fc transgenic mice or via specific genetic deletion of IL-6Ra on neutrophils conferred protection against both diseases. Taken together, our findings suggest that a maternal HFD induces neonatal LGSI that predisposes to sLRI and subsequent asthma via neutrophil-mediated IL-6 trans-signaling.

Metabolic alterations, a hallmark of cancer, enable tumor cells to adapt to their environment by modulating glucose, lipid, and amino acid metabolism, which fuels rapid growth and contributes to treatment resistance. In primary breast cancer, metabolic shifts such as the Warburg effect and enhanced lipid synthesis are closely linked to chemotherapy failure. Similarly, metastatic lesions often display distinct metabolic profiles that not only sustain tumor growth but also confer resistance to targeted therapies and immunotherapies. The review emphasizes two major aspects: the mechanisms driving metabolic resistance in both primary and metastatic breast cancer, and how the unique metabolic environments in metastatic sites further complicate treatment. By targeting distinct metabolic vulnerabilities at both the primary and metastatic stages, new strategies could improve the efficacy of existing therapies and provide better outcomes for breast cancer patients.

Obesity is associated with an increased risk for 13 different cancers. The increased risk for cancer in obesity is mediated by obesity-associated changes in the immune system. Obesity has distinct effects on different types of inflammation that are tied to tumorigenesis. For example, obesity promotes chronic inflammation in adipose tissue that is tumor-promoting in peripheral tissues. Conversely, obesity inhibits acute inflammation that rejects tumors. Obesity therefore promotes cancer by differentially regulating chronic versus acute inflammation. Given that obesity is chronic, the initial inflammation in adipose tissue will lead to systemic inflammation that could induce compensatory anti-inflammatory reactions in peripheral tissues to suppress chronic inflammation. The overall effect of obesity in peripheral tissues is therefore dependent on the duration and severity of obesity. Adipose tissue is a complex tissue that is composed of many cell types in addition to adipocytes. Further, adipose tissue cellularity is different at different anatomical sites throughout the body. Consequently, the sensitivity of adipose tissue to obesity is dependent on the anatomical location of the adipose depot. For example, obesity induces more inflammation in visceral than subcutaneous adipose tissue. Based on these studies, the mechanisms by which obesity promotes tumorigenesis are multifactorial and immune cell type-specific. The objective of our paper is to discuss the cellular mechanisms by which obesity promotes tumorigenesis by regulating distinct types of inflammation in adipose tissue and the tumor microenvironment.

Metabolic reprogramming (MR) in cancer (CA) has been a focus of intense research in the recent two decades. This phenomenon has attracted great interest because it offers potential targets for cancer therapy. To capture the intellectual landscape of this field, we conducted a bibliometric analysis to assess the scientific output, major contributors, and trends in the MR/CA research.

We performed a systematic search using the Web of Science to retrieve articles published on MR of cancer from 2006 until 2023. The bibliometric tools such as Biblioshiny, VOSviewer, and Microsoft Excel were used to identify the most prolific authors, institutions, citation patterns, and keywords. We also used co-citation analysis to map the conceptual structure of the field and identify influential publications. Furthermore, we examined the literature by analyzing publication years, citations, and research impact factors.

A total of 4,465 publications about MR/CA were retrieved. Publications on MR/CA increased rapidly from 2006 to 2023. Frontiers in Oncology published the most papers, while Cell Metabolism had the most citations. Highly cited papers were mainly published in Cancer Cell, Nature, Cell, Science and Cell Metabolism. China and the United States led the way in publications and contributed the most to MR/CA research. The University of Texas System, Chinese Academy of Sciences, and Fudan University were the most productive institutions. The profitable authors were Deberardinis Ralph J and Chiarugi Paola. The current topics included MR in tumorigenesis and progression of CA, MR of tumor cells and tumor microenvironment, the effect of MR on the CA treatment, the underlying mechanisms of MR (such as gene regulation, epigenetics, extracellular vesicles, and gut microbiota), and the modulation of MR. Some topics such as tumor microenvironment, lipid MR, circular RNA, long noncoding RNA, exosome, prognostic model, and immunotherapy may be the focus of MR/CA research in the next few years.

This study evaluated the global scientific output in the field of MR/CA research, analyzing its quantitative characteristics. It identified some significant and distinguished papers and compiled information regarding the current status and evolving trends of MR/CA research.

Abnormal metabolism in tumor cells represents a potential target for tumor therapy. In this regard, dietary restriction (DR) or its combination with anticancer drugs is of interest as it can impede the growth of tumor cells. In addition to its effects on tumor cells, DR also plays an extrinsic role in restricting tumor growth by regulating immune cells. NK cells are innate immune cells involved in tumor immunosurveillance. However, it remains uncertain whether DR can assist NK cells in controlling tumor growth. In this study, we demonstrate that DR effectively inhibits metastasis of melanoma cells to the lung. Consistent with this, the regression of tumors induced by DR was minimal in mice lacking NK cells. Single-cell RNA sequencing analysis revealed that DR enriched a rejuvenated subset of CD27+CD11b+ NK cells. Mechanistically, DR activated a regulatory network involving the transcription factor Eomesodermin (Eomes), which is essential for NK-cell development. First, DR promoted the expression of Eomes by optimizing mTORC1 signaling. The upregulation of Eomes revived the subset of functional CD27+CD11b+ NK cells by counteracting the expression of T-bet and downstream Zeb2. Moreover, DR enhanced the function and chemotaxis of NK cells by increasing the accessibility of Eomes to chromatin, leading to elevated expression of adhesion molecules and chemokines. Consequently, we conclude that DR therapy enhances tumor immunity through nontumor autonomous mechanisms, including promoting NK-cell tumor immunosurveillance and activation.

The older American population is rapidly increasing, and millions of older adults will be cancer survivors with comorbidities. This population faces specific challenges regarding treatment and has unique clinical needs. Recognizing this need, the National Cancer Institute, in collaboration with the National Institute on Aging, hosted a webinar series, entitled Cancer, Aging, and Comorbidities. This commentary provides a reflection of 5 thematic areas covered by the webinar series, which was focused on improving cancer treatment for older adults with cancer and comorbidities: 1) the impact of comorbidities on treatment tolerability and patient outcomes; 2) the impact of comorbidities on cancer clinical trial design; 3) the development of wearable devices in measuring comorbidities in cancer treatment; 4) the effects of nutrition and the microbiome on cancer therapy; and 5) the role of senescence and senotherapy in age-related diseases. Advances have been made in these areas, however, many gaps and challenges exist and are discussed in this commentary. To improve cancer survivorship in older populations with comorbidities, aging and comorbidities must be jointly considered and incorporated across the spectrum of cancer research. This includes more basic research of the mechanisms linking comorbidities and cancer development and treatment response, building critical resources and infrastructure (eg, preclinical models and patient samples), conducting clinical trials focused on the older population, integrating geriatric assessment into cancer treatment, and incorporating novel technologies, such as wearable devices, into clinical trials and cancer care.