This review was written to be included in the Special Collection 'Therapy Ultrasound: Medicine's Swiss Army Knife?' The purpose of this review is to provide basic presentation and interpretation of the fundamentals of hyperthermia biology, as it pertains to uses of therapeutic ultrasound. The fundamentals are presented but in the setting of a translational interpretation and a view toward the future. Subjects that require future research and development are highlighted. The effects of hyperthermia are time and temperature dependent. Because intra-tumoral temperatures are non-uniform in tumors, one has to account for differential biologic effects in different parts of a tumor that occur simultaneously during and after hyperthermia.

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.

Pancreatic cancer is a highly aggressive gastrointestinal malignancy, often termed the "king of cancers" due to its notoriously high mortality rate. Its clinical characteristics, including late diagnosis, low surgical resectability, high recurrence rates, significant chemoresistance, and poor prognosis have collectively driven the persistent rise in incidence and mortality. Despite ongoing advancements in therapeutic strategies, the management of pancreatic cancer, particularly at advanced stages, remains challenging. Chemotherapy remains the mainstay of current treatment. However, the prevalent problem of chemotherapy resistance poses a significant obstacle to effective treatment. Metabolic reprogramming, characterized by alterations in glucose metabolism, lipid biosynthesis, and amino acid utilization, supports the high energy demands and rapid proliferation of cancer cells. Emerging evidence suggests that these metabolic changes, possibly mediated by epigenetic mechanisms, also contribute to tumorigenesis and metastasis. These findings highlight the critical role of metabolic alterations in pancreatic cancer pathogenesis. This review explores the relationship between metabolic reprogramming and chemotherapy resistance, discussing underlying mechanisms and summarizing preclinical studies and drug development targeting metabolism. The aim is to provide a comprehensive perspective on potential therapeutic strategies for pancreatic cancer.

Deregulated energy metabolism is a hallmark of cancer, characterized by increased glycolytic flux. Cancer-specific modification of 6-phosphofructo-1-kinase (PFK) impairs its ability to regulate the enzyme's activity which increases glycolytic flux. Consequently, excessive cytosolic NADH formation triggers a harmful redox imbalance in cancer cells, which is rapidly neutralized by the formation of lactic acid and superoxide (SOX). To learn more about deregulated glycolysis in cancer cells, a supercomputer used the atomic model of the crystal structure of human PFK1 for virtual screening a database of 4.5 million compounds by docking with the catalytic binding sites of the enzyme. The screening revealed two compounds capable of reducing modified, cancer-specific PFK1 activity and simultaneously suppressing lactate and SOX formation. A dose-dependent inhibition was observed in the cells treated by compounds in the following tumorigenic cells: Jurkat (Acute T cells leukemia); Caco-2 (colorectal adenocarcinoma); COLO 829 (melanoma); and MDA-MB-231 (breast gland adenocarcinoma). In addition, two selected compounds assessed for cytostatic and cytotoxic activity showed no negative effects on tumorigenic cells. However, during incubation, the strengths of inhibitions continuously decreased, both during lactate and SOX formation. No such effects were observed if compounds were sequentially submitted to the cells at low concentrations every 24 hours. Additional experiments performed by Jurkat cells revealed reduced respiration and glycolysis rates in the cells treated with compounds concerning the untreated cells. Inhibition of modified cancer-specific PFK1 activity reduces deregulated glycolytic flux, prevents abundant cytosolic NADH formation, and restores redox balance thus simultaneously preventing the formation of deleterious effects of lactate and SOX, two crucial players in cancer initiation and development.

The treatment landscape of non-small-cell lung cancer (NSCLC) is evolving rapidly, driven by advances in the development of targeted agents and immunotherapies. Despite this progress, some patients have suboptimal responses to treatment, highlighting the need for new therapeutic strategies. In the past decade, the important role of the tumour microenvironment (TME) in NSCLC progression, metastatic dissemination and response to treatment has become increasingly evident. Understanding the complexity of the TME and its interactions with NSCLC can propel efforts to improve current treatment modalities, overcome resistance and develop new treatments, which will ultimately improve the outcomes of patients. In this Review, we provide a comprehensive view of the NSCLC TME, examining its components and highlighting distinct archetypes characterized by spatial niches within and surrounding tumour nests, which form complex neighbourhoods. Next, we explore the interactions within these components, focusing on how inflammation and immunosuppression shape the dynamics of the NSCLC TME. We also address the emerging influences of patient-related factors, such as ageing, sex and health disparities, on the NSCLC-TME crosstalk. Finally, we discuss how various therapeutic strategies interact with and are influenced by the TME in NSCLC. Overall, we emphasize the interconnectedness of these elements and how they influence therapeutic outcomes and tumour progression.

The pH balance between extracellular and intracellular space is crucial for a multitude of cellular processes. Real-time observation of pH fluctuations in the range 4-9 in live cells and tissues in a sensitive, non-invasive manner has become feasible with advances in pH quantification by organic dyes, genetically encoded fluorescent proteins, and DNA-based probes. We discuss mechanisms through which pH affects cell cycle, transcription, senescence, neurotransmission, glycolipid-lectin driven endocytosis, tissue remodelling, immune responses, and GPCR signalling. Growth factor-stimulated acidification of the extracellular space notably triggers enzymatic reactions like desialylation at the plasma membrane that control processes involving cell migration and bone resorption. Research into the role of pH in cellular physiology continues to be a fertile ground for discovery that underscores its fundamental importance.

The extracellular matrix (ECM) plays a pivotal role in immunomodulation, providing structural and biochemical cues that shape immune cell function. In pathological conditions like cancer and chronic inflammation, dysregulated remodeling often results in altered ECM composition and architecture, with fibrillar alignment being a hallmark linked to disease progression. Here, how ECM alignment influences dendritic cell (DC) behavior using 3D biomimetic collagen matrices with controlled fibril anisotropy is investigated. This results show that immature DCs in aligned matrices exhibited increased expression of CD86 and HLA-DR with elevated secretion of CXCL8 and CCL2 chemokines, which may enhance immune cell recruitment. However, transcriptomic and metabolomic analysis revealed significant downregulation of oxidative phosphorylation and an insufficient compensatory shift toward glycolysis, resulting in reduced ATP production. This metabolic constraint correlated with impaired/reduced DC migratory speed and distance. In contrast, mature DCs displayed minimal sensitivity to ECM alignment, maintaining uniform differentiation and functional profiles across matrix conditions. T-cell coculture experiments revealed that ECM alignment dampens T-cell activation and proliferation, likely through direct modulation of T-cell behavior. These findings highlight the stage-specific effects of ECM alignment on DC function, highlighting its role in DC immunomodulation, with implications for therapeutic development in cancer and other pathological contexts.

Cancer stem cells (CSCs) are a distinct subpopulation of cancer cells with the capacity to constantly self-renew and differentiate, and they are the main driver in the progression of cancer resistance and relapse. The tumor microenvironment (TME) constructed by CSCs is the "soil" adapted to tumor growth, helping CSCs evade immune killing, enhance their chemical resistance, and promote cancer progression.

We aim to elaborate the tight connection between CSCs and immunosuppressive components of the TME. We attempt to summarize and provide a therapeutic strategy to eradicate CSCs based on the destruction of the tumor ecological niche.

This review is focused on three main key concepts. First, we highlight that CSCs recruit and transform normal cells to construct the TME, which further provides ecological niche support for CSCs. Second, we describe the main characteristics of the immunosuppressive components of the TME, targeting strategies and summarize the progress of corresponding drugs in clinical trials. Third, we explore the multilevel insights of the TME to serve as an ecological niche for CSCs.

Tumor cells transmit various immunosuppressive signals and induce a dysfunctional state in T cells, which essentially leads to immune escape and tumor progression. However, developing effective strategies to counteract the domestication of T cells by tumor cells remains a challenge. Here, we prepared pH-responsive lipid nanoparticles (NL/PLDs) co-loaded with PCSK9 shRNA, lonidamine (LND), and low-dose doxorubicin (DOX). NL/PLDs can awaken domesticated T cells function by sending pro-activation, pro-recognition, and pro-killing signals by increasing tumor immunogenicity, increasing the expression of major histocompatibility complex I (MHC-I) on tumor cells, and alleviating the suppression effect of tumor-secreted lactic acid (LA) on the T cell effector function, respectively. In melanoma-bearing mice, NL/PLDs effectively relieved tumor immunosuppressive microenvironment (TIME) and enhanced the antitumor immunity mediated by CD8+ T cells. Furthermore, when combined with aPD-1, NL/PLDs demonstrated strong antitumor effects and increased immunotherapeutic efficacy. This regulatory strategy provides new insights for enhancing immunotherapy by regulating tumor immunosuppressive signals and shows significant potential for clinical tumor treatment.

SLC16A3, belonging to the SLC16 gene family, is involved in the transportation of monocarboxylate. SLC16A family members play important roles in tumorigenesis, nonetheless, the specific involvement of SLC16A3 in tumor prognosis and diagnosis in human cancers remains unelucidated. This study dealt with the exploration of SLC16A3 expression in human pan-cancer and its significance regarding disease prognosis. For this investigation, the mRNA expression data of SLC16A3 were acquired from the TCGA and the GTEx datasets. The Kaplan-Meier plots, univariate Cox regression, and the ROC curve were employed for assessing the prognostic and diagnostic significance of SLC16A3 in pan-cancer. Furthermore, the cBioPortal database was used to analyze the SLC16A3 genomic alterations. Moreover, the association of the infiltration of immune cells and immune checkpoint genes with SLC16A3 was analyzed by the TIMER database. Gene Ontology and KEGG pathway analysis were employed to explore the function of SLC16A3 in pan-cancer. The resulting data demonstrated that SLC16A3 mRNA expression was overexpressed in most cancers and its protein expression was also high across diverse cancer types. Moreover, upregulated SLC16A3 expression was linked to poor OS and PFI of certain cancers. Cox regression analysis further indicated that SLC16A3 is a risk factor for patients with PAAD, CESC, LUSC, LUAD, CHOL, LGG, MESO, and OSCC. The ROC curve revealed that SLC16A3 exhibited a high accuracy (AUC > 0.9) in BRCA, CHOL, ESCA, GBM, and KIRC prediction. Moreover, the acquired data indicated that in pan-cancer, the SLC16A3 expression exhibited correlations with immune checkpoint genes and immune cells. These findings collectively suggest that SLC16A3 holds promise as a biomarker for diagnostic and prognostic purposes in pan-cancer.

The advent of immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, offering life-saving benefits to tumor patients. However, the utilize of ICI agents is often accompanied by immune-related adverse events (irAEs), among which cardiovascular toxicities have attracted more and more attention. ICI induced cardiovascular toxicities predominantly present as acute myocarditis and chronic atherosclerosis, both of which are driven by excessive immune activation. Reprogramming of T cells and macrophages has been demonstrated as a pivotal factor in the pathogenesis of these complications. Therapeutic strategies targeting glycolysis, fatty acid oxidation, reactive oxygen species (ROS) production and some other key signaling have shown promise in mitigating immune hyperactivation and inflammation. In this review, we explored the intricate mechanisms underlying ICI-induced cardiovascular toxicities and highlighted the protective potential of immune reprogramming. We emphasize the roles of T cell and macrophage reprogramming in the heart and vasculature, showcasing their contributions to both short-term and long-term regulation of cardiovascular health. Ultimately, a deeper understanding of these processes will not only enhance the safety of ICIs but also pave the way for innovative strategies to manage immune-related toxicities in cancers therapy.

As the end-product of glycolysis, lactate serves as a regulator of protein lactylation in addition to being an energy substrate, metabolite, and signaling molecule in cancer. The reprogramming of glucose metabolism and the Warburg effect in breast cancer results in extensive lactate production and accumulation, making it likely that lactylation in tumor tissue is also abnormal. This review summarizes evidence on lactylation derived from studies of lactate metabolism and disease, highlighting the role of lactate in the tumor microenvironment of breast cancer and detailing the levels of lactylation and cancer-promoting mechanisms across various tumors. The roles of lactate and lactylation, along with potential intervention mechanisms, are presented and discussed, offering valuable insights for future research on the role of lactylation in tumors.

Targeting cancer cell metabolism has emerged as a promising strategy to reverse the immunosuppressive tumor microenvironment (TME). Aerobic glycolysis, the dominant metabolic pathway in cancer cells, leads to glucose depletion and the accumulation of immunosuppressive metabolites such as lactate, ultimately limiting the efficacy of conventional immunotherapies. In this study, metal phenolic-networks (MPNs) are developed by coating zinc oxide (ZnO) nanoparticles with epigallocatechin gallate (EGCG) to modulate cancer metabolism for TME reprogramming and immune activation. Under acidic conditions, MPNs release Zn2+ ions and EGCG, inhibiting both glycolysis and mitochondrial metabolism, effectively regulating the metabolic ability of cancer cells. Furthermore, severe starvation stress induced by dual metabolic inhibition triggers immunogenic cell death (ICD) without the need for conventional ICD inducers. Consequently, MPN treatment reverses the immunosuppressive TME through dual metabolic regulation and ICD, which induces dendritic cell maturation, cytotoxic T cell activation, and regulatory T cell suppression. These findings highlight the potential of combining metabolic therapy with immunotherapy as a novel strategy to enhance antitumor immunity and overcome the limitations of current cancer treatments.

This review discusses reprogramming the breast tumor immune microenvironment from an immunosuppressive cold state to an immunologically active hot state. A complex interplay is revealed, in which the accumulation of metabolic byproducts-such as lactate, reactive oxygen species (ROS), and ammonia-is shown to impair T-cell function and promote tumor immune escape. It is demonstrated that the tumor microenvironment (TME) is dominated by immunosuppressive cytokines, including interleukin-10 (IL-10), transforming growth factorβ (TGFβ), and IL-35. Notably, IL-35 is produced by regulatory T cells and breast cancer cells. The conversion of conventional T cells into IL-35-producing induced regulatory T cells, along with the inhibition of pro-inflammatory cytokine secretion, contributes to the suppression of anti-tumor immunity. It is further demonstrated that key immune checkpoint molecules-such as PD-1, PDL1, CTLA-4, TIM-3, LAG-3, and TIGIT-are upregulated within the TME, leading to Tcell exhaustion and diminished immune responses. The blockade of these checkpoints is shown to restore T-cell functionality and is proposed as a strategy to convert cold tumors into hot ones with robust effector cell infiltration. The therapeutic potential of chimeric antigen receptor (CAR)T cell therapy is also explored, and targeting specific tumor-associated antigens, such as glycoproteins and receptor tyrosine kinases, is highlighted. It is suggested that CART cell efficacy can be enhanced by combining these cells with immune checkpoint inhibitors and other immunomodulatory agents, thereby overcoming the barriers imposed by the immunosuppressive TME. Moreover, the role of the microbiome in regulating estrogen metabolism and systemic inflammation is reviewed. Alterations in the gut microbiota are shown to affect the TME, and microbiome-based interventions are proposed as an additional means to facilitate the cold-to-hot transition. It is concluded that by targeting the metabolic and immunological pathways that underpin immune suppression-through combination strategies involving checkpoint blockade, CART cell therapies, and microbiome modulation-the conversion of the breast TME from cold to hot can be achieved. This reprogramming is anticipated to enhance immune cell infiltration and function, thereby improving the overall efficacy of immunotherapies and leading to better clinical outcomes for breast cancer patients.

To investigate the effect of acidic urine (pH ≤ 5.5) on disease recurrence or progression in patients with nonmuscle-invasive bladder cancer (NMIBC) undergoing transurethral resection of bladder tumor (TURBT) followed by intravesical Bacillus Calmette-Guérin (BCG) induction therapy.

A total of 578 patients with intermediate- and high-risk NMIBC who underwent intravesical BCG induction after initial TURBT between May 2003 and April 2021 were included. Patients were subdivided into low (pH ≤ 5.5) and high (pH > 5.5) urine pH groups.

Patients with acidic urine showed higher fasting plasma glucose levels (p = 0.017), higher serum uric acid level (p = 0.011), lower estimated glomerular filtration rates (p = 0.022), and higher rates of abnormal urinary cytology (p = 0.021), but no significant differences were observed in context of adverse clinicopathological features. During a median follow-up period of 56 months, the acidic urine group had a lower recurrence-free survival rate than the high urine pH group (p = 0.009). In terms of disease progression, there was no difference according to urine pH status.

Acidic urine was associated with disease recurrence after intravesical BCG induction for NMIBC, despite no differences in adverse clinicopathological features according to urine acidity.

Immunotherapy has transformed the landscape of cancer treatment but remains largely ineffective for patients with pancreatic ductal adenocarcinoma (PDAC). Some patients, however, show improved outcomes when treated with a combination of immunotherapy and chemotherapy. Here, we conducted deep serum proteome analysis to investigate the protein profiles of PDAC patients and changes during this combinatorial treatment. Utilizing an advanced serum workflow, we quantified 1,011 proteins across 211 samples from 62 patients. Glycolytic enzymes were associated with survival in anti-PD-1-treated patients, with their abundances significantly correlating with expression levels in tumor biopsies. Notably, a set of protein biomarkers was found to be highly predictive of survival in anti-PD-1-treated patients (area under the curve [AUC] = 0.91). Overall, our data demonstrate the potential of deep serum proteomics for precision medicine, offering a powerful tool to guide patient selection for treatment through minimally invasive serum protein biomarker measurements.

In humans, aging is an inevitable consequence of diminished growth processes after reaching maturity. The high order of biomolecules in cells and tissues is continuously disturbed by numerous physical and chemical destructive impacts. Host-derived oxidant-based cytotoxic agents (reactive species, transition free metal ions, and free heme) contribute considerably to this damage. These agents are under the control of immediately acting antagonizing principles, which are important to ensure cell and tissue homeostasis. In this review, I apply the concept of host-derived cytotoxic agents and their interplay with antagonizing principles to the aging process. During aging, energy metabolism and the supply of tissues with dioxygen and nutrients are increasingly disturbed. In addition, a chronic inflammatory state develops, a condition known as inflammaging. The balance between oxidant-based cytotoxic agents and protective mechanisms is analyzed depending on age-based physiological alterations in ATP production. Disturbances in this balance are associated with the development of age-related diseases and comorbidities. An enhanced production of reactive species from dysfunctional mitochondria, alterations in cellular redox homeostasis, and adaptations to hypoxia are highlighted. Examples of how disturbances between oxidant-based cytotoxic agents and antagonizing principles contribute to the pathogenesis of diseases in persons of advanced age are given.

Glioblastoma, the most common and aggressive primary malignant brain tumor, is characterized by a high rate of recurrence, disability, and lethality. Therefore, there is a pressing need to develop more effective prognostic biomarkers and treatment approaches for glioblastoma. Lactylation, an emerging form of protein post-translational modification, has been closely associated with lactate, a metabolite of glycolysis. Since the initial identification of lactylation sites in core histones in 2019, accumulating evidence has shown the critical role that lactylation plays in glioblastoma development, assessment of poor clinical prognosis, and immunosuppression, which provides a fresh angle for investigating the connection between metabolic reprogramming and epigenetic plasticity in glioblastoma cells. The objective of this paper is to present an overview of the metabolic and epigenetic roles of lactylation in the expanding field of glioblastoma research and explore the practical value of developing novel treatment plans combining targeted therapy and immunotherapy.

T-cell therapy advances have stimulated the development of bioprocesses to address the specialized needs of cell therapy manufacturing. During concentrated cell washing, the cells are frequently exposed to transiently reduced oxygen, temperature, pH, and nutrient levels. Longer durations of these conditions can be caused by process deviations or, if they are not harmful, be used to ease the scheduling of process stages during experiments as well as manufacturing.

To avoid unpredictable impacts on T-cell quality during bioprocessing, we measured the influences of such environmental exposures generated by settling 250 million activated human T cells per mL, for up to 6 h at temperatures from 4 to 37°C.

The measured glucose concentration decreased to as low as 0.5 mM and the pH to 6, while lactate increased up to 55 mM. The concentrated cell conditions at 37°C resulted in by far the greatest losses in viable cell numbers with, on average, only 58% and 41% of the cells recovered after 3 and 6 h, respectively. Likewise, their subsequent cell expansion cultures were substantially reduced even after only 3 h of exposure, and with decreased percentages of central memory T cells and increased percentages of effector memory and effector T cells. Although under similar environmental conditions at room temperatures, the negative impacts of high cell concentrations were greatly diminished for up to 3 h. At 4°C the transient conditions were less extreme, and the cells well maintained for 6 h.

Overall, when developing processes and devices for T-cell therapy manufacturing that involve concentrated cells, the results of this study indicate that more practically feasible room temperatures can be used for up to 3 h to obtain high viable cell recoveries whereas lower temperatures such as 4°C should be used if there is a need for more prolonged concentrated T-cell conditions.

The fate of immune cells is fundamentally linked to their metabolic program, which is also influenced by the metabolic landscape of their environment. The tumor microenvironment represents a unique system for intercellular metabolic interactions, where tumor-derived metabolites suppress effector CD8+ T cells and promote tumor-promoting macrophages, reinforcing an immune-suppressive niche. This review will discuss recent advancements in metabolism research, exploring the interplay between various metabolites and their effects on immune cells within the tumor microenvironment.

The complex composition and dynamic change of the tumor microenvironment (TME), mainly consisting of tumor cells, immune cells, stromal cells, and extracellular components, significantly impede the effector function of cytotoxic T lymphocytes (CTL), thus representing a major obstacle for tumor immunotherapies. In this review, we summarize and discuss the impacts and underlying mechanisms of major elements in the TME (different cell types, extracellular matrix, nutrients and metabolites, etc.) on the infiltration, survival, and effector functions of T cells, mainly CD8+ CTLs. Moreover, we also highlight recent advances that may potentiate endogenous antitumor immunity and improve the efficacy of T cell-based immunotherapies in patients with cancer by manipulating components inside/outside of the TME. A deeper understanding of the effects and action mechanisms of TME components on the tumor-eradicating ability of CTLs may pave the way for discovering new targets to augment endogenous antitumor immunity and for designing combinational therapeutic regimens to enhance the efficacy of tumor immunotherapies in the clinic.

The role of human Papillomavirus (HPV) in metabolic reprogramming is implicated in the development and progression of cervical cancer. During carcinogenesis, cancer cells modify various metabolic pathways to generate energy and sustain their growth and development. Cervical cancer, one of the most prevalent malignancies affecting women globally, involves metabolic alterations such as increased glycolysis, elevated lactate production, and lipid accumulation. The oncoproteins, primarily E6 and E7, which are encoded by high-risk HPVs, facilitate the accumulation of several cancer markers, promoting not only the growth and development of cancer but also metastasis, immune evasion, and therapy resistance. HPV oncoproteins interact with cellular MYC (c-MYC), retinoblastoma protein (pRB), p53, and hypoxia-inducible factor 1α (HIF-1α), leading to the induction of metabolic reprogramming and favour the Warburg effect. Metabolic reprogramming enables HPV to persist for an extended period and accelerates the progression of cervical cancer. This review summarizes the role of HPV oncoproteins in metabolic reprogramming and their contributions to the development and progression of cervical cancer. Additionally, this review provides insights into how metabolic reprogramming opens avenues for novel therapeutic strategies, including the discovery of new and repurposed drugs that could be applied to treat cervical cancer.

Cancer treatment era has been revolutionized by the novel therapeutic methods such as immunotherapy in recent years. Immunotherapy-based approaches are considered effective and reliable methods that has brought hope to eradicate certain cancers. Nonetheless, there are some issues, considered as critical obstacles in successful cancer immunotherapy. Such issues are attributed to the ability of the tumor cells in providing a tolerant microenvironment that impairs the immune responses, and help the cancer cells evade the immunogenic cell death. It has been suggested that the re-activation and maintenance of effector immune cells may become possible by metabolic reprogramming. Several signaling pathways have been noticed with the possibility of metabolic reprogramming of tumor-specific T cells, to overcome the metabolic restrictions in the tumor microenvironment; and among them, AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptors (PPAR) have been investigated the most as the main energy sensors and regulators of mitochondrial biogenesis. The synergic effects of AMPK activators and/or PPAR agonists in cancer immunotherapy have been reported. In this review, we compare the roles of AMPK activators and PPAR agonists, and the efficacy of their combination in metabolic reprogramming of cytotoxic T cells in favoring cancer immunotherapy.

The malignant tumor is a serious disease threatening human life. Increasing studies have confirmed that the tumor microenvironment (TME) is composed of a variety of complex components that precisely regulate the interaction of tumor cells with other components, allowing tumor cells to continue to proliferate, resist apoptosis, evade immune surveillance and clearance, and metastasis. However, the characteristics of each component and their interrelationships remain to be deeply understood. To target TME, it is necessary to deeply understand the role of various components of TME in tumor growth and search for potential therapeutic targets. Herein, we innovatively classify the TME into physical microenvironment (such as oxygen, pH, etc.), mechanical microenvironment (such as extracellular matrix, blood vessels, etc.), metabolic microenvironment (such as glucose, lipids, etc.), inflammatory microenvironment and immune microenvironment. We introduce a concise but comprehensive classification of the TME; depict the characteristics of each component in TME; summarize the existing methods for detecting each component in TME; highlight the current strategies and potential therapeutic targets for TME; discuss current challenges in presenting TME and its clinical applications; and provide our prospect on the future research direction and clinical benefits of TME.

Lactic acid (LA) accumulation in tumor microenvironments (TME) has been implicated in immune suppression and tumor progress. Diverse roles of LA have been elucidated, including microenvironmental pH regulation, signal transduction, post-translational modification, and metabolic remodeling. This review summarizes LA functions within TME, focusing on the effects on tumor cells, immune cells, and stromal cells. Reducing LA levels is a potential strategy to attack cancer, which inevitably affects the physiological functions of normal tissues. Alternatively, transporting LA into the mitochondria as an energy source for immune cells is intriguing. We underscore the significance of LA in both tumor biology and immunology, proposing the burning of LA as a potential therapeutic approach to enhance antitumor immune responses.

In the domain of addressing cancer resistance, challenges such as limited effectiveness and treatment resistance remain persistent. Hypoxia is a key feature of solid tumors and is strongly associated with poor prognosis in cancer patients. Another significant portion of the development of acquired drug resistance is attributed to tumor stemness. Cancer stem cells (CSCs), a small tumor cell subset with self-renewal and proliferative abilities, are crucial for tumor initiation, metastasis, and intra-tumoral heterogeneity. Studies have shown a significant association between hypoxia and CSCs in the context of tumor resistance. Recent studies reveal a strong link between hypoxia and tumor stemness, which together promote tumor survival and progression during treatment. This review elucidates the interplay between hypoxia and CSCs, as well as their correlation with resistance to therapeutic drugs. Targeting pivotal genes associated with hypoxia and stemness holds promise for the development of novel therapeutics to combat tumor resistance.

Immunotherapy has revolutionized cancer treatment, yet its efficacy is frequently compromised by metabolic mechanisms that drive resistance. Understanding how tumor metabolism shapes the immune microenvironment is essential for developing effective therapeutic strategies. This review examines key metabolic pathways influencing immunotherapy resistance, including glucose, lipid, and amino acid metabolism. We discuss their impact on immune cell function and tumor progression, highlighting emerging therapeutic strategies to counteract these effects. Tumor cells undergo metabolic reprogramming to sustain proliferation, altering the availability of essential nutrients and generating toxic byproducts that impair cytotoxic T lymphocytes (CTLs) and natural killer (NK) cell activity. The accumulation of lactate, deregulated lipid metabolism, and amino acid depletion contribute to an immunosuppressive tumor microenvironment (TME). Targeting metabolic pathways, such as inhibiting glycolysis, modulating lipid metabolism, and restoring amino acid balance, has shown promise in enhancing immunotherapy response. Addressing metabolic barriers is crucial to overcoming immunotherapy resistance. Integrating metabolic-targeted therapies with immune checkpoint inhibitors may improve clinical outcomes. Future research should focus on personalized strategies to optimize metabolic interventions and enhance antitumor immunity.

Historically, lactate has been considered merely a metabolic byproduct. However, recent studies have revealed that lactate plays a much more dynamic role, acting as an immune signaling molecule that influences cellular communication, through the process of "lactate shuttling." Lactylation, a novel post-translational modification, is directly derived from lactate and represents an emerging mechanism through which lactate exerts its effects on cellular function. It has been shown to directly affect immune cells by modulating the activation of pro-inflammatory and anti-inflammatory pathways. This modification influences the expression of key immune-related genes, thereby impacting immune cell differentiation, cytokine production, and overall immune response. In this review, we focused on the role of lactate and lactylation in the dysregulation of immune responses in psoriasis and its relapse. Additionally, we discuss the potential applications of targeting lactate metabolism and lactylation modifications in the treatment of psoriasis, alongside the investigation of artificial intelligence applications in advancing lactate and lactylation-focused drug development, identifying therapeutic targets, and enabling personalized medical decision-making. The significance of this review lies in its comprehensive exploration of how lactate and lactylation contribute to immune dysregulation, offering a novel perspective for understanding the metabolic and epigenetic changes associated with psoriasis. By identifying the roles of these pathways in modulating immune responses, this review provides a foundation for the development of new therapeutic strategies that target these mechanisms.

Lactate, the end product of both anaerobic and aerobic glycolysis in proliferating and growing cells-with the latter process known as the Warburg effect-is historically considered a mere waste product of cell and tissue metabolism. However, research over the past ten years has unveiled multifaceted functions of lactate that critically shape and impact cellular biology. Beyond serving as a fuel source, lactate is now known to influence gene expression through histone modification and to function as a signaling molecule that impacts a wide range of cellular activities. These properties have been particularly studied in the context of both adaptive and innate immune responses. Here, we review the diverse roles of lactate in the regulation of the immune system during homeostasis and disease pathogenesis (including cancer, infection, cardiovascular diseases, and autoimmunity). Furthermore, we describe recently proposed therapeutic interventions for manipulating lactate metabolism in human diseases.

As the final product of glycolysis, lactate serves as an energy substrate, metabolite, and signaling molecule in various diseases and mediates lactylation, an epigenetic modification that occurs under both physiological and pathological conditions. Lactylation is a crucial mechanism by which lactate exerts its functions, participating in vital biological activities such as glycolysis-related cellular functions, macrophage polarization, and nervous system regulation. Lactylation links metabolic regulation to central nervous system (CNS) diseases, such as traumatic brain injury, Alzheimer's disease, acute ischemic stroke, and schizophrenia, revealing the diverse functions of lactylation in the CNS. In the future, further exploration of lactylation-associated enzymes and proteins is needed to develop specific lactylation inhibitors or activators, which could provide new tools and strategies for the treatment of CNS diseases.

Ovarian cancer (OC) is one of the three most common malignant tumors of the female reproductive system, with the highest mortality rate among gynecologic malignancies. Like other tumors, OC cells undergo metabolic reprogramming phenomenon and convert glucose metabolism into "aerobic glycolysis" and generate a high concentration of lactate, i.e., the "Warburg effect", which provides a large amount of energy and corresponding intermediary metabolites for their survival, reproduction and metastasis. Numerous studies have shown that targeted inhibition of aerobic glycolysis and lactate metabolism is a promising strategy to enhance the sensitivity of cancer cells to immunotherapy. Therefore, this review summarizes the metabolic features of glycolysis in OC cells and highlights how abnormal lactate concentration affects the differentiation, metabolism, and function of infiltrating immune cells, which contributes to immunosuppression, and how targeted inhibition of this phenomenon may be a potential strategy to enhance the therapeutic efficacy of OC.

Intercellular communication is fundamental to multicellular life and a core determinant of outcomes during viral infection, where the common goals of virus and host for persistence and replication are generally at odds. Hosts rely on encoded innate and adaptive immune responses to detect and clear viral pathogens, while viruses can exploit or disrupt these pathways and other intercellular communication processes to enhance their spread and promote pathogenesis. While virus-induced signaling can result in systemic changes to the host, striking alterations are observed within the cellular microenvironment directly surrounding a site of infection, termed the virus microenvironment (VME). Mechanisms employed by viruses to condition their VMEs are emerging and are critical for understanding the biology and pathologies of viral infections. Recent advances in experimental approaches, including proteomic methods, have enabled study of the VME in unprecedented detail. In this review article, we provide a primer on proteomic approaches used to study how viral infections alter intercellular communication, highlighting the ways in which these approaches have been implemented and the exciting biology they have uncovered. First, we consider the different molecules secreted by an infected cell, including proteins, either soluble or contained within extracellular vesicles, and metabolites. We further discuss the modalities of interactions facilitated by alteration at the cell surface of infected cells, including immunopeptide presentation and interactions with the extracellular matrix. Finally, we review spatial profiling approaches that have allowed distinguishing how specific subpopulations of cells within a VME respond to infection and alter their protein composition, discussing valuable insights these methods have offered.

Leukemias are a class of human cancers that originate from hematopoietic progenitors and are characterized by extensive remodeling of the immune microenvironment. Leukemic cells, on transformation, acquire the ability to evade immune recognition but, despite undergoing genetic and epigenetic changes, retain their characteristic immature immune signature. For this and other reasons, leukemias are often refractory to immune therapies. In the present Review, we cover these areas as a means of improving outcomes from a deeper understanding of immune rewiring, inflammatory signaling and the barriers to successful implementation of immune therapies.

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.

It is well known that T-cell metabolism and function are intimately linked. Metabolic reprogramming is a dynamic process that provides the necessary energy and biosynthetic precursors while actively regulating the immune response of T cells. As such, aberrations and dysfunctions in metabolic (re)programming, resulting in altered metabolic endotypes, may have an impact on disease pathology in various contexts. With the increasing demand for personalized and highly specialized medicine and immunotherapy, understanding metabolic profiles and T-cell subset dependence on specific metabolites will be crucial to harness the therapeutic potential of immunometabolism and T cell bioenergetics. In this review, we dissect metabolic alterations in different T-cell subsets in autoimmune and viral inflammation, T cell and non-T-cell malignancies, highlighting potential anchor points for future treatment and therapeutic exploitation.

To comprehensively analyze the association between preoperative maximum standardized uptake value (SUVmax) on 18F-fluorodeoxyglucose positron emission tomography-computed tomography and postoperative recurrence in resected non-small cell lung cancer (NSCLC) using machine learning (ML) and statistical approaches.

This retrospective study included 643 patients who had undergone NSCLC resection. ML models (random forest, gradient boosting, extreme gradient boosting, and AdaBoost) and a random survival forest model were developed to predict postoperative recurrence. Model performance was evaluated using the receiver operating characteristic (ROC) AUC and concordance index (C-index). Shapley additive explanations (SHAP) and partial dependence plots (PDPs) were used to interpret model predictions and quantify feature importance. The relationship between SUVmax and recurrence risk was evaluated by using a multivariable Cox proportional hazards model.

The random forest model showed the highest predictive performance (ROC AUC, 0.90; 95% CI, 0.86 to 0.97). The SHAP analysis identified SUVmax as an important predictor. The PDP analysis showed a nonlinear relationship between SUVmax and recurrence risk, with a sharp increase at SUVmax 2-5. The random survival forest model achieved a C-index of 0.82. A permutation importance analysis identified SUVmax as the most important feature. In the Cox model, increased SUVmax was associated with a higher risk of recurrence (adjusted hazard ratio, 1.03 [95% CI, 1.00 to 1.06]).

Preoperative SUVmax showed significant predictive value for postoperative recurrence after NSCLC resection. The nonlinear relationship between SUVmax and recurrence risk, with a sharp increase at relatively low SUVmax values, suggests its potential as a sensitive biomarker for early identification of high-risk patients. This may contribute to more precise assessments of the risk of recurrence and personalized treatment strategies for NSCLC.

Tumors employ a range of strategies to evade detection and eradication by the host's immune system. These include downregulating antigen expression, altering antigen presentation processes, and inhibiting immune checkpoint pathways. etc. Adoptive Cell Therapy (ACT) represents a strategy that boosts anti-tumor immunity. This is achieved by amplifying or genetically engineering immune cells, which are either sourced from the patient or a donor, in a laboratory setting. Subsequently, these cells are reintroduced into the patient to bolster their immune response against cancer. ACT has successfully restored anti-tumor immune responses by amplifying the activity of T cells from patients or donors. This review focuses on the mechanisms underlying tumor escape, including alterations in tumor cell antigens, the immunosuppressive tumor microenvironment (TME), and modulation of immune checkpoint pathways. It further explores how ACT can avddress these factors to enhance therapeutic efficacy. Additionally, the review discusses the application of gene-editing technologies (such as CRISPR) in ACT, highlighting their potential to strengthen the anti-tumor capabilities of T cells. Looking forward, the personalized design of ACT, combined with immune checkpoint inhibitors and targeted therapies, is expected to significantly improve treatment outcomes, positioning this approach as a key strategy in the field of cancer immunotherapy.

Tumors are inherently embedded in systemic physiology, which contributes metabolites, signaling molecules, and immune cells to the tumor microenvironment. As a result, any systemic change to host metabolism can impact tumor progression and response to therapy. In this review, we explore how factors that affect metabolic health, such as diet, obesity, and exercise, influence the interplay between cancer and immune cells that reside within tumors. We also examine how metabolic diseases influence cancer progression, metastasis, and treatment. Finally, we consider how metabolic interventions can be deployed to improve immunotherapy. The overall goal is to highlight how metabolic heterogeneity in the human population shapes the immune response to cancer.

Metabolic reprogramming in cancer cells involves changes in glucose metabolism, glutamine utilization, and lipid production, as well as promoting increased cell proliferation, survival, and immune resistance by altering the tumor microenvironment. Our study analyzes metabolic reprogramming in neoplastically transformed cells, focusing on changes in glucose metabolism, glutaminolysis, and lipid synthesis. Moreover, we discuss the therapeutic potential of targeting cancer metabolism, focusing on key enzymes involved in glycolysis, the pentose phosphate pathway, and amino acid metabolism, including lactate dehydrogenase A, hexokinase, phosphofructokinase and others. The review also highlights challenges such as metabolic heterogeneity, adaptability, and the need for personalized therapies to overcome resistance and minimize adverse effects in cancer treatment. This review underscores the significance of comprehending metabolic reprogramming in cancer cells to engineer targeted therapies, personalize treatment methodologies, and surmount challenges, including metabolic plasticity and therapeutic resistance.

In colorectal cancer (CRC), increased numbers of tumor-infiltrating CD4+ regulatory T (Treg) cells correlate with tumor development, immunotherapy failure, and poor prognosis. To assess how CRC tumors directly modulate Treg cell differentiation, we developed an in vitro co-culture system using CD4+ T cells from Foxp3eGFP mice and CRC tumor-derived organoids. Co-culture resulted in a significant increase in Treg cell numbers. RNA-sequencing identified a distinct transcriptional profile of CRC organoid-induced Treg cells, with upregulation of genes associated with CRC Treg cells in vivo. High expression of genes upregulated in CRC organoid-induced Treg cells correlates with shorter progression-free intervals and overall survival in CRC patients. Human CRC organoids similarly induced Treg cells with enhanced suppressive capacity and upregulated genes linked to CRC Treg cells in vivo. This model provides insights into how CRC tumors modulate CD4+ T cell differentiation and can identify approaches to disrupt Treg cells and stimulate anti-tumor immunity.

Energy metabolism is indispensable for sustaining physiological functions in living organisms and assumes a pivotal role across physiological and pathological conditions. This review provides an extensive overview of advancements in energy metabolism research, elucidating critical pathways such as glycolysis, oxidative phosphorylation, fatty acid metabolism, and amino acid metabolism, along with their intricate regulatory mechanisms. The homeostatic balance of these processes is crucial; however, in pathological states such as neurodegenerative diseases, autoimmune disorders, and cancer, extensive metabolic reprogramming occurs, resulting in impaired glucose metabolism and mitochondrial dysfunction, which accelerate disease progression. Recent investigations into key regulatory pathways, including mechanistic target of rapamycin, sirtuins, and adenosine monophosphate-activated protein kinase, have considerably deepened our understanding of metabolic dysregulation and opened new avenues for therapeutic innovation. Emerging technologies, such as fluorescent probes, nano-biomaterials, and metabolomic analyses, promise substantial improvements in diagnostic precision. This review critically examines recent advancements and ongoing challenges in metabolism research, emphasizing its potential for precision diagnostics and personalized therapeutic interventions. Future studies should prioritize unraveling the regulatory mechanisms of energy metabolism and the dynamics of intercellular energy interactions. Integrating cutting-edge gene-editing technologies and multi-omics approaches, the development of multi-target pharmaceuticals in synergy with existing therapies such as immunotherapy and dietary interventions could enhance therapeutic efficacy. Personalized metabolic analysis is indispensable for crafting tailored treatment protocols, ultimately providing more accurate medical solutions for patients. This review aims to deepen the understanding and improve the application of energy metabolism to drive innovative diagnostic and therapeutic strategies.

As important innate immune cells, natural killer (NK) cells play an essential role in resisting pathogen invasion and eliminating transformed cells. However, the hypoxic microenvironment caused by disease conditions is an important physicochemical factor that impairs NK cell function. With the increasing prominence of NK cells in immunotherapy, there has been a surge of interest in developing biological means through which NK cells may overcome the inhibition caused by hypoxia in disease conditions. Although the effects of hypoxic conditions in shaping the functions of NK cells have been increasingly recognized and investigated, reviews have been scantly. A comprehensive understanding of how NK cells adapt to hypoxia can provide valuable insights into how the functional capacity of NK cells may be restored. This review focuses on the functional alterations of NK cells in response to hypoxia. It delineates the mechanisms by which NK cells adapt to hypoxia at the transcriptional, metabolic, translational levels. Furthermore, given the complexity of the hypoxic microenvironment, we also elucidated the effects of key hypoxic metabolites on NK cells. Finally, this review discusses the current clinical therapies derived from targeting hypoxic NK cells. The study of NK cell adaptation to hypoxia has yielded new insights into immunotherapy. These insights may lead to development of novel strategies to improve the treatment of infectious diseases and cancer.