Chronic arsenic exposure enhances the probability of lung cancer with the underlying mechanisms remain unknown. Glutamine-driven synthetic metabolism, including nucleotide synthesis, amino acid production, TCA cycle replenishment, glutathione synthesis, and lipid biosynthesis, is crucial for both cancer initiation and progression. This study demonstrated that chronic exposure to 0.1 μM arsenite for as long as 36 weeks induced malignant transformation in human bronchial epithelial cells (BEAS-2B). Metabolomics were used to systematically disclose metabolic characteristics in arsenic-transformed malignant (As-TM) cells. Significantly changed metabolites were enriched in alanine, aspartate and glutamate metabolism, arginine biosynthesis, glutamine and glutamate metabolism, glutathione metabolism, butanoate metabolism, TCA cycle, and arginine and proline metabolism. It is worth noting that glutamate located at the intersection of the enriched metabolism pathways. Glutamine deprivation attenuated the oncogenic phenotypes, including capacity of wound healing and proliferation, in As-TM cells. And the expression levels of mRNA and proteins associated with glutamine metabolism-related transporters and enzymes, including SLC7A11, GCLM, and GCLC, were significantly increased, with SLC7A11 exhibiting the most substantial increase. Moreover, arsenite transformation progressively elevated SLC7A11 mRNA and protein levels over time. The SLC7A11 inhibitor sulfasalazine remarkably attenuated arsenite-induced oncogenic phenotypes. Collectively, our data suggest that chronic arsenite exposure enhances glutamine metabolism through upregulation of SLC7A11, thereby promoting cell proliferation and malignant transformation. These results provide new insights for preventive and therapeutic strategies for lung cancer linked to arsenic exposure.

Dietary interventions can influence tumor growth by restricting tumor-specific nutritional requirements, altering the nutrient availability in the tumor microenvironment, or enhancing the cytotoxicity of anticancer drugs. Metabolic reprogramming of tumor cells, as a significant hallmark of tumor progression, has a profound impact on immune regulation, severely hindering tumor eradication. Dietary interventions can modify tumor metabolic processes to some extent, thereby further improving the efficacy of tumor treatment. In this review, we emphasize the impact of dietary patterns on tumor progression. By exploring the metabolic differences of nutrients in normal cells versus cancer cells, we further clarify how dietary patterns influence cancer treatment. We also discuss the effects of dietary patterns on traditional treatments such as immunotherapy, chemotherapy, radiotherapy, and the gut microbiome, thereby underscoring the importance of precision nutrition.

The tumor microenvironment (TME) is a complex ecosystem that plays a crucial role in tumor progression and response to therapy. The metabolic characteristics of the TME are fundamental to its function, influencing not only cancer cell proliferation and survival but also the behavior of immune cells within the tumor. Metabolic reprogramming-where cancer cells adapt their metabolic pathways to support rapid growth and immune evasion-has emerged as a key factor in cancer immunotherapy. Recently, the potential of engineered bacteria in cancer immunotherapy has gained increasing recognition, offering a novel strategy to modulate TME metabolism and enhance antitumor immunity. This review summarizes the metabolic properties and adaptations of tumor and immune cells within the TME and summarizes the strategies by which engineered bacteria regulate tumor metabolism. We discuss how engineered bacteria can overcome the immunosuppressive TME by reprogramming its metabolism to improve antitumor therapy. Furthermore, we examine the advantages, potential challenges, and future clinical translation of engineered bacteria in reshaping TME metabolism.

Gastrointestinal (GI) cancers remain a leading cause of cancer-related mortality worldwide, with metabolic reprogramming recognized as a central driver of tumor progression and therapeutic resistance. Among the key regulatory layers, N6-methyladenosine (m6A) RNA modification-mediated by methyltransferases (writers such as METTL3/14), RNA-binding proteins (readers like YTHDFs and IGF2BPs), and demethylases (erasers including FTO and ALKBH5), plays a pivotal role in controlling gene expression and metabolic flux in the tumor context. Concurrently, the gut microbiota profoundly influences GI tumorigenesis and immune evasion by modulating metabolite availability and remodeling the tumor microenvironment. Recent evidence has uncovered a bidirectional crosstalk between microbial metabolites and m6A methylation: microbiota-derived signals dynamically regulate m6A deposition on metabolic and immune transcripts, while m6A modifications, in turn, regulate the stability and translation of key mRNAs such as PD-L1 and FOXP3. This reciprocal interaction forms self-reinforcing epigenetic circuits that drive tumor plasticity, immune escape, and metabolic adaptation. In this review, we dissect the molecular underpinnings of the microbiota-m6A-metabolism axis in GI cancers and explore its potential to inform novel strategies in immunotherapy, metabolic intervention, and microbiome-guided precision oncology.

High reactive oxygen species (ROS) serve as important signaling molecules in the tumor microenvironment, and their excessive generation is closely associated with tumor growth, drug resistance, and metastasis of tumors. Rrecently, probes based on 1,3-cyclohexanedione have been proposed, enabling real-time monitoring of ROS levels in the tumor microenvironment. Herein, as a proof of concept, we aimed at synthesizing a novel tumor diagnostic probe, 68Ga-NOTA-cRGD, by connecting NOTA and the tumor-targeting peptide cRGD with a 1,3-cyclohexanedione group that specifically undergoes cross-linking with sulfenic acid, to enhance the targeting and prolong the imaging time of the probe in tumors. Moreover, the study also evaluated the capability of the synthesized probe in both in vitro and in vivo experiments. The results indicated that the radiolabeling process was efficient and stable, and the stability of the probe under physiological conditions was also outstanding. Compared to the control probe 68Ga-NOTA-cRGD-1 lacking 1,3-cyclohexanedione, the experimental probe 68Ga-NOTA-cRGD-2 not only exhibited significant improvements in cell uptake efficiency, tumor imaging contrast, and biodistribution characteristics but also demonstrated enhanced cell affinity and a prolonged in vivo biological half-life. The addition of 1,3-cyclohexanedione enhanced the probe's tumor-targeting capability, resulting in higher uptake in A549 tumor cells. In conclusion, this study confirmed the crucial role of 1,3-cyclohexanedione in prolonging tumor targeting. It is anticipated to provide a theoretical foundation and experimental support for the development of more efficient probes in the future.

Cancer immunotherapy is transforming the treatment landscape of both hematological and solid cancers. Although T-cell-based adoptive cell transfer (ACT) therapies have demonstrated initial success, several recurrent obstacles limit their long-term anti-tumor efficacy, including: (1) lack of antigen specificity; (2) poor long-term survival of transplanted T cells in vivo; and (3) a hostile tumor microenvironment (TME). While numerous approaches have been explored to enhance the antigen specificity of Chimeric Antigen Receptor (CAR) T-cell therapies, the field still lacks an effective strategy to optimize the long-term retention and in vivo expansion of engrafted T cells within the TME-a critical factor for the durable efficacy of T-cell-based immunotherapies for both blood and solid cancers. Here, we hypothesize that the success of CAR T-cell therapy can be enhanced by targeting donor T cells' ability to compete with cancer cells for key nutrients, thereby overcoming T-cell exhaustion and sustaining durable anti-tumor function in the TME. To explore this hypothesis, we first provide a comprehensively review of the current understanding of the metabolic interactions (e.g., glucose metabolism) between T cells and tumor cells. To address the challenges, we propose an innovative strategy: utilizing nutrient gene therapy (genetic overexpression of glucose transporter 1, GLUT1) to fortify the metabolic competency of adoptive CAR T-cells, deprive tumors of critical metabolites and ATP, and disrupt the TME. Altogether, our proposed approach combining precision medicine (adoptive CAR T-cell therapy) with tumor metabolism-targeting strategies offers a promising and cost-effective solution to enhance the efficacy and durability of ACT therapies, ultimately improving outcomes for cancer patients.

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.

Chemical and mechanical cues within the extracellular matrix (ECM) can initiate intracellular signaling that changes an array of fundamental cell functions. In recent work, studies of cell-ECM adhesion have deepened to include the influence of the physical ECM on cell metabolism. Since many biological processes involve metabolic programs, changes to cellular metabolism in response to cues in the ECM can have marked effects on cell health. In this review, we describe molecular mechanisms associated with cell-ECM adhesion that are key players in metabolism-induced changes to cell behaviors, including migration. We first review how changes to metabolite availability in the extracellular environment or manipulation of metabolic machinery in cells impact focal adhesions. We then connect this work to recent findings regarding the reverse relationship, namely, how the manipulation of focal adhesion proteins or integrins feeds back to alter cell metabolism. Finally, we consider the latest findings from studies that describe how the mechanical properties of the ECM, primarily stiffness and confinement, alter cellular metabolism. We identify key areas of future investigation that may elucidate the molecular drivers that permit cells to respond to mechanical and chemical ECM cues by reprogramming their metabolism to better inform future diagnostics and therapeutics for disease states.

Exposure to metal(loid)s and glucose metabolism may influence the progression of gastric precancerous lesions (GPLs) or gastric cancer (GC), but their combined effects remain unclear. Our study aimed to elucidate the combined impact of metal (including metalloid and trace element) exposure and disturbances in glucose metabolism on the progression of GPLs and GC. From a prospective observational cohort of 1829 individuals, their metal(loid) levels and blood metabolism were analysed via inductively coupled plasma‒mass spectrometry and targeted metabolomics gas chromatography‒mass spectrometry, respectively. From healthy normal controls (NC) or GPLs to GC, we observed that the aluminum and arsenic levels decreased, whereas the vanadium, titanium and rubidium levels increased, but the iron, copper, zinc and barium levels initially decreased but then increased; these changes were not obvious from the NC to GPL group. With respect to glucose homeostasis, most metabolites decreased, except for phosphoenolpyruvate (PEP), which increased. Multiple logistic regression analysis revealed that titanium and phosphoenolpyruvate might be risk factors for GPLs, that barium is a protective factor for GC, and that D-glucaric acid might be a protective factor for GPLs and GC. Selenium, vanadium, titanium, succinate, maleate, isocitrate, PEP, and the tricarboxylic acid cycle (TCA) had good predictive potential for GPL and GC. Additionally, metal(loid)s such as arsenic, titanium, barium, aluminum, and vanadium were significantly correlated with multiple glucose metabolites involved in the TCA cycle in the GPL and GC groups. Our findings imply that metal(loid) exposure disrupts glucose metabolism, jointly influencing GPL and GC progression.

Metastasis plays a significant role in the high mortality rates associated with cancer and is usually the endpoint of a series of sequential and dynamic events. A crucial step in metastasis development and progression is the formation of a premetastatic niche (PMN), which provides a conducive microenvironment for the settlement and colonization of disseminated tumor cells at distant metastatic sites. Extensive research has demonstrated the significance of macrophage populations within primary tumors in promoting metastatic progression. Nevertheless, the contribution of macrophages at secondary sites to the regulation of PMN formation is frequently overlooked. This review systematically explores the role of macrophages in priming the PMN to facilitate cancer metastasis. Additionally, we provide a compendium of existing strategies to target macrophages in cancer therapy.

We aimed to evaluate the biodistribution and specificity of 68Ga-DOTA-TAT and RHO-TAT using MGC-803 and HT-29 tumor cells as well as tumor-xenografted nude mice and to demonstrate its application in positron emission tomography (PET) imaging. The in vitro evaluation of 68Ga-DOTA-TAT was assessed in MGC-803 and HT-29 cell lines, and the in vivo evaluation of 68Ga-DOTA-TAT was also performed in mice bearing MGC-803 or HT-29 tumors, respectively. Fluorescence microscopy was also employed to evaluate the specificity of RHO-TAT in vitro in MGC-803 and HT-29 cells as well as ex vivo in tumor slices of the corresponding tumor models. The in vivo imaging differences between 68Ga-DOTA-TAT and 18F-FDG in MGC-803 and HT-29 tumors were also studied. The biodistribution and micro-PET results demonstrated significant uptake of 68Ga-DOTA-TAT in non-FDG-avid MGC-803 tumors, whereas there was negligible uptake in FDG-avid HT-29 tumors. RHO-TAT showed superior fluorescence microscopy imaging effects in MGC-803 cells and tumor slices but not in HT-29 cells and tumor slices, which were consistent with the in vivo results. 68Ga-DOTA-TAT combined with 18F-FDG can be applied noninvasively in cancers with PET imaging for potential patient selection and stratification. We demonstrated a higher binding of 68Ga-DOTA-TAT and RHO-TAT to MGC-803 cells as well as to non-FDG-avid MGC-803 xenografted tumors and a lower binding to HT-29 cells and FDG-avid xenografted tumors. These results suggest that TAT has the potential to be a ligand for targeting certain tumors.

The tumor microenvironment (TME) influences cancer cell metabolism and survival. However, how immune and stromal cells respond to metabolic stress in vivo, and how nutrient limitations affect therapy, remains poorly understood. Here, we introduce Dual Ribosome Profiling (DualRP) to simultaneously monitor translation and ribosome stalling in multiple tumor cell populations. DualRP reveals that cancer-fibroblast interactions trigger an inflammatory program that reduces amino acid shortages during glucose starvation. In immunocompetent mice, we show that serine and glycine are essential for optimal T cell function and that their deficiency impairs T cell fitness. Importantly, immune checkpoint blockade therapy imposes amino acid restrictions specifically in T cells, demonstrating that therapies create distinct metabolic demands across TME cell types. By mapping codon-resolved ribosome stalling in a cell‑type‑specific manner, DualRP uncovers metabolic crosstalk that shapes translational programs. DualRP thus offers a powerful, innovative approach for dissecting tumor cell metabolic interplay and guiding combined metabolic-immunotherapeutic strategies.

Adaptive resistance to immunotherapy remains a significant challenge in cancer treatment. The reshaping of the tumor immune microenvironment in response to therapeutic pressures is a crucial factor contributing to this resistance. In this study, by comprehensive metabolic profiling of tumor tissues, we identified elevated itaconate in response to anti-PD-1 therapy as an adaptive resistance mechanism that promoted immune escape and tumor progression. CD8+ T-cell-derived IFNγ induced a significant upregulation of cis-aconitate decarboxylase 1 (ACOD1) in macrophages via the JAK-STAT1 pathway, thereby rewiring the Krebs cycle toward itaconate production. In murine models, macrophage-specific deletion of Acod1 increased the antitumor efficacy of anti-PD-1 therapy and improved survival. Additionally, itaconate and its derivative, 4-octyl itaconate, suppressed the tumor antigen presentation and cross-priming ability of dendritic cells, resulting in the impairment of antigen-specific T-cell antitumor responses. In summary, these findings identify an IFNγ-dependent immunometabolic mechanism of anti-PD-1 resistance, providing a promising strategy for combination therapy. Significance: Elevated itaconate production by macrophages induced by IFNγ is a critical negative feedback immunoregulatory metabolic response to anti-PD-1 immunotherapy that inhibits the cross-priming function of dendritic cells and confers immunotherapy resistance.

Metabolic reprogramming is pivotal in malignant transformation and cancer progression. Tumor metabolism is shaped by a complex interplay of both intrinsic and extrinsic factors that are not yet fully elucidated. It is of great value to unravel the complex metabolic activity of tumors in patients. Metabolic flux analysis (MFA) is a versatile technique for investigating tumor metabolism in vivo, it has increasingly been applied to the assessment of metabolic activity in cancer in the past decade. Stable-isotope tracing have shown that human tumors use diverse nutrients to fuel central metabolic pathways, such as the tricarboxylic acid cycle and macromolecule synthesis. Precisely how tumors use different fuels, and the contribution of alternative metabolic pathways in tumor progression, remain areas of intensive investigation. In this review, we systematically summarize the evidence from in vivo stable- isotope tracing in tumors and describe the catabolic and anabolic processes involved in altered tumor metabolism. We also discuss current challenges and future perspectives for MFA of human cancers, which may provide new approaches in diagnosis and treatment of cancer.

Tumor-associated macrophages (TAMs) play a pivotal role in the tumor microenvironment (TME), actively contributing to the formation of an immunosuppressive niche that fosters tumor progression. Consequently, there has been a growing interest in targeting TAMs as a promising avenue for cancer therapy. Recent advances in the field of immunometabolism have shed light on the influence of metabolic adaptations on macrophage physiology in the context of cancer. Here, we discuss the key metabolic pathways that shape the phenotypic diversity of macrophages. We place special emphasis on how metabolic reprogramming impacts the activation status of TAMs and their functions within the TME. Additionally, we explore alterations in TAM metabolism and their effects on phagocytosis, production of cytokines/chemokines and interaction with cytotoxic T and NK immune cells. Moreover, we examine the application of nanomedical approaches to target TAMs and assess the clinical significance of modulating the metabolism of TAMs as a strategy to develop new anti-cancer therapies. Taken together, in this comprehensive review article focusing on TAMs, we provide invaluable insights for the development of effective immunotherapeutic strategies and the enhancement of clinical outcomes for cancer patients.

Adenosine 5'-triphosphate (ATP) plays a pivotal role as an essential intermediate in energy metabolism, influencing nearly all biological metabolic processes. Cancer cells predominantly rely on glycolysis for ATP production, differing significantly from normal cells. Real-time in situ monitoring and rapid response to intracellular ATP levels offers more valuable insights into cancer cell physiology. Herein, we report a novel ratiometric luminescent probe, Ru-Rho, comprised of a ruthenium(II)-based complex and rhodamine 6G (Rho 6G) with excellent water solubility and photostability. Notably, Ru-Rho selectively responds to ATP at acidic conditions, matching the need of monitoring ATP under the acidic intracellular environment of cancer cells. Moreover, the fast ratiometric detection and imaging of ATP under single wavelength excitation improve the detection accuracy. Ru-Rho has been effectively utilized not only for ratio imaging ATP in cells and zebrafish, but also for assessing the efficacy of glycolysis-inhibiting anticancer drugs in intracellular levels, which accelerates the screening process for anticancer drugs and supports the development of new therapeutic agents. The design strategy based on transition metal ruthenium(II) complexes opens a new pathway for constructing ATP luminescent probes, allowing for better adaptation to complex detection requirements.

Ovarian cancer (OC) ranks as the most lethal gynaecological malignancy worldwide, with early diagnosis being crucial yet challenging. Current diagnostic methods like transvaginal ultrasound and blood biomarkers show limited sensitivity/specificity. This study aimed to identify and validate serum metabolic biomarkers for OC diagnosis using the largest cohort reported to date.

We constructed a large-scale OC-associated cohort of 1432 subjects, including 662 OC, 563 benign ovarian disease, and 207 healthy control subjects, across retrospective (n = 1073) and set-aside validation (n = 359) cohorts. Serum metabolic fingerprints (SMFs) were recorded using nanoparticle-enhanced laser desorption/ionization mass spectrometry (NELDI-MS). A diagnostic panel was developed through machine learning of SMFs in the discovery cohort and validated in independent verification and set-aside validation cohorts. The identified metabolic biomarkers were further validated using liquid chromatography MS and their biological functions were assessed in OC cell lines.

We identified a metabolic biomarker panel including glucose, histidine, pyrrole-2-carboxylic acid, and dihydrothymine. This panel achieved consistent areas under the curve (AUCs) of 0.87-0.89 for distinguishing between malignant and benign ovarian masses across all cohorts, and improved to AUCs of 0.95-0.99 when combined with risk of ovarian malignancy algorithm (ROMA). In vitro validation provided initial biological context for the metabolic alterations observed in our diagnostic panel.

Our study established a reliable serum metabolic biomarker panel for OC diagnosis with potential clinical translations. The NELDI-MS based approach offers advantages of fast analytical speed (∼30 s/sample) and low cost (∼2-3 dollars/sample), making it suitable for large-scale clinical applications.

MOST (2021YFA0910100), NSFC (82421001, 823B2050, 824B2059, and 82173077), Medical-Engineering Joint Funds of Shanghai Jiao Tong University (YG2021GD02, YG2024ZD07, and YG2023ZD08), Shanghai Science and Technology Committee Project (23JC1403000), Shanghai Institutions of Higher Learning (2021-01-07-00-02-E00083), Shanghai Jiao Tong University Inner Mongolia Research Institute (2022XYJG0001-01-16), Sichuan Provincial Department of Science and Technology (2024YFHZ0176), Innovation Research Plan by the Shanghai Municipal Education Commission (ZXWF082101), Innovative Research Team of High-Level Local Universities in Shanghai (SHSMU-ZDCX20210700), Basic-Clinical Collaborative Innovation Project from Shanghai Immune Therapy Institute, Guangdong Basic and Applied Basic Research Foundation (2024A1515013255).

Nutrient stress represents an important barrier for anti-tumour immunity, and tumour interstitial fluid often contains metabolites that hinder immune function. However, it is difficult to isolate the effects of tumour nutrient stress from other suppressive factors. Thus, we used a chemically defined cell culture medium based on the metabolomic profile of tumour interstitial fluid: tumour interstitial fluid medium (TIFM). Culture of CD8+ T cells in TIFM limited cell expansion and impaired CD8+ T cell effector functions upon restimulation, suggesting that tumour nutrient stress alone is sufficient to drive T cell dysfunction. We identified phosphoethanolamine (pEtn), a phospholipid intermediate, as a driver of T cell dysfunction. pEtn dampened T cell receptor signalling by depleting T cells of diacylglycerol required for T cell receptor signal transduction. The reduction of pEtn accumulation in tumours improved intratumoural T cell function and tumour control, suggesting that pEtn accumulation plays a dominant role in immunosuppression in the tumour microenvironment.

Tumor metabolism plays a pivotal role in shaping immune responses within the tumor microenvironment influencing tumor progression, immune evasion, and the efficacy of cancer therapies. Radiotherapy has been shown to impact both tumor metabolism and immune modulation, often inducing immune activation through damage-associated molecular patterns and the STING pathway. In this study, we analyse the particular characteristics of the tumour metabolic microenvironment and its effect on the immune microenvironment. We also review the changes in the metabolic and immune microenvironment that are induced by radiotherapy, with a focus on metabolic sensitisation to the effects of radiotherapy. Our aim is to contribute to the development of research ideas in the field of radiotherapy metabolic-immunological studies.

Solid cancer contains a complicated communication network between cancer cells and components in the tumor microenvironment (TME), significantly influencing the progression of cancer. Exosomes function as key carriers of signaling molecules in these communications, including the intricate signalings of tumor-associated macrophages (TAMs) on cancer cells and the TME. With their natural lipid bilayer structures and biological activity that relates to their original cell, exosomes have emerged as efficient carriers in studies on cancer therapy. Intrigued by the heterogeneity and plasticity of both macrophages and exosomes, we regard macrophage-derived exosomes in cancer as a double-edged sword. For instance, TAM-derived exosomes, educated by the TME, can promote resistance to cancer therapies, while macrophage-derived exosomes generated in vitro have shown favorable potential in cancer therapy. Here, we depict the reasons for the heterogeneity of TAM-derived exosomes, as well as the manifold roles of TAM-derived exosomes in cancer progression, metastasis, and resistance to cancer therapy. In particular, we emphasize the recent advancements of modified macrophage-derived exosomes in diverse cancer therapies, arguing that these modified exosomes are endowed with unique advantages by their macrophage origin. We outline the challenges in translating these scientific discoveries into clinical cancer therapy, aiming to provide patients with safe and effective treatments.

Drug screening of primary tumor cells directly assesses the drug efficacy on specific tumors, promoting personalized cancer treatment. The application of a microfluidic platform has realized drug screening using a limited amount of biopsy samples for cancer precision medicine. However, all the techniques face an inevitable issue of not all the primary tumor cells being cancer cells. Here, a system is introduced that integrates single-cell identification and drug screening on one semiconductor chip so that both drug efficacy on cancer cells and drug toxicity on noncancerous cells can be obtained simultaneously. An integrated circuit is built on the semiconductor chip for single-cell electric impedance sensing (IC-ECIS) of ultra-weak signals for distinguishing cancer cells from noncancerous cells without affecting cell vitality. Single-cell identification is validated using breast, lung, and liver cell lines as well as liver cancer specimens from clinical patients. The accuracy on commercial cell lines is ≈80%, and the diagnostic results of tumor tissues are consistent with clinical pathology results. Drug screening is run on the same chip after single cell identification for dual evaluation of drug efficacy and toxicity in both breast cancer models and clinical liver cancer patients. The on-chip drug screening is confirmed with off-chip counterpart experiments in breast cell lines. The effectiveness or ineffectiveness of a drug screened on the IC-ECIS chip demonstrated consistency in the presence or absence of specific mutations in the drug-related genes determined via exome sequencing of individual liver tumors, validating the method for precision medicine.

Immune-based treatment strategies have emerged across solid organ malignancies largely with the development of immune checkpoint inhibitors. To date, these strategies have not improved clinical outcomes in pancreatic ductal adenocarcinoma (PDAC).

Here, we perform a systematic review to summarize available evidence for recent immune-based treatment strategies in PDAC. We analyze trends in activated clinical trials queried from clinicaltrials.gov in the years 2020-2022. We review study design, sponsorship, and trends in the phase of development. There is a growing emergence of multiple new classes of immune-based targets and combination strategies in early-phase development.

Immune-based clinical trials in PDAC are highly collaborative including primarily stakeholders in government, industry, and academic medical centers. In this period, a majority of trials have integrated a non-randomized design (83.2%), including a trend towards an increase in Phase I/II clinical trials. This analysis found a growing list of studies using combinations including inhibitors of vascular endothelial growth factors (VEGF), an expanded set of vaccine-based strategies, and the use of Bispecific T-Cell Engagers (BiTEs). Immune checkpoint inhibitors have been a mainstay of combination strategies including the use of new immune checkpoint inhibitors (CD40, TIGIT).

Immune-based strategies in PDAC have expanded across new targets and the complexities of combinatory approaches. Integrating this work across key stakeholders remains of critical importance to improve clinical outcomes.

Epithelioid angiomyolipoma (EAML) is a tumor with malignant potential, as evidenced by its pathological features. Further investigation into its additional characteristics, particularly in imaging, is of great significance for non-invasive detection methods to understand its malignant potential. In this context, we present a case study of a 47-year-old male patient with a right renal EAML. The patient underwent nephrectomy but subsequently developed liver metastasis. Next-generation sequencing confirmed mutations of tuberous sclerosis 2 (TSC2) in both the primary and metastatic lesions. Consequently, the patient received maintenance treatment with the mTOR inhibitor, everolimus. However, treatment was discontinued after six months due to disease progression. Subsequent 18F-FDG PET/CT imaging revealed a large heterogeneous hypermetabolic mass in the liver, along with two other hypermetabolic metastases near the liver capsule. The patient's prognosis was poor, with indicators such as TSC2 mutation, tumor necrosis, high Ki-67 expression, and α-SMA-negative fibroblasts. Despite reoperation, the patient still succumbed to disease progression. The occurrence of malignant metastatic EAML detected using 18F-FDG PET/CT imaging is infrequent. We conducted a comprehensive review of the relevant literature on 18F-FDG PET/CT imaging for EAML. Notably, this article emphasizes that elevated 18F-FDG uptake in EAML may serve as a novel indicator of malignant EAML.

Disulfidptosis and ferroptosis are recently identified programmed cell deaths for tumor therapy, both of which highly depend on the intracellular cystine/cysteine transformation on the cystine transporter solute carrier family 7 member 11/glutathione/glutathione peroxidase 4 (SLC7A11/GSH/GPX4) antioxidant axis. However, disulfidptosis and ferroptosis are usually asynchronous due to the opposite effect of cystine transport on them. Herein, systematic glucose deprivation, by both inhibiting upstream glucose uptake and promoting downstream glucose consumption, is proposed to synchronously evoke disulfidptosis and ferroptosis. As an example, Au nanodots and Fe-apigenin (Ap) complexes coloaded FeOOH nanoshuttles (FeOOH@Fe-Ap@Au NSs) are employed to regulate the SLC7A11/GSH/GPX4 axis for performing disulfidptosis- and ferroptosis-mediated tumor therapy synchronously. In this scenario, Au nanodots exhibit glucose oxidase-like activity when consuming massive glucose. Meanwhile, Ap can inhibit glucose uptake by downregulating glucose transporter 1, depriving glucose fundamentally. The systematical glucose deprivation limits the supplement of NADPH and suppresses cystine/cysteine transformation on the SLC7A11/GSH/GPX4 axis, thus solving the contradiction of cystine transport on disulfidptosis and ferroptosis. In addition, the efficient delivery of exogenous iron ions by FeOOH@Fe-Ap@Au NSs and self-supplied H2O2 through Au nanodots-catalytic glucose oxidation facilitate intracellular Fenton reaction and therewith help to amplify ferroptosis. As a result of synchronous occurrence of disulfidptosis and ferroptosis, FeOOH@Fe-Ap@Au NSs exhibit good efficacy in an ovarian cancer therapeutic model.

EGFR-targeting mAbs are essential for managing rat sarcoma virus wild-type metastatic colorectal cancer (mCRC), but their limited efficacy necessitates exploring immunologic and metabolic factors influencing response. This study evaluated glutamine metabolism targeting with EGFR inhibition to identify response biomarkers in patients with prior anti-EGFR treatment progression.

We conducted a phase I/II trial in patients with KRAS wild-type mCRC, combining panitumumab (6 mg/kg) and CB-839 (600 mg/kg or 800 mg/kg), hypothesizing that the dual inhibition of glutamine metabolism and MAPK signaling would enhance outcomes. As study correlatives, we investigated the B-cell activation signature "B-score" and glutamine PET as potential treatment response biomarkers.

The combination of panitumumab and CB-839 was tolerable with manageable side effects, including grade 4 hypomagnesemia in four patients, a known panitumumab-related event. Two patients achieved partial response, and five had stable disease, with a 41% disease control rate. Median progression-free survival and overall survival were 1.84 and 8.87 months, respectively. A positive correlation between "B-score" and lesion size reduction suggested its association with clinical benefit (partial response and stable disease). Lower "B-score" correlated with greater tumor avidity for glutamine by PET, indicating B-cell activation sensitivity to glutamine depletion.

The combination of CB-839 and panitumumab showed safety and promising preliminary responses, but the study closed early due to CB-839 development termination. The B-cell activation signature "B-score" emerged as a potential biomarker for EGFR and glutaminase inhibition in mCRC, warranting further studies. These findings suggest opportunities to improve immune response and therapies in glutaminolysis-dependent tumors.

Richter syndrome (RS) is the transformation of chronic lymphocytic leukemia (CLL) into a high-grade lymphoma with previously unknown metabolic features. Transcriptomic data from primary CLL and RS samples, as well as RS-patient-derived xenografts, highlighted cellular metabolism as one of the most significant differentially expressed processes. Activity assays of key enzymes confirmed the intense metabolic rewiring of RS cells, which is characterized by an elevated rate of Krebs cycle, oxidative phosphorylation, and glutamine metabolism. These pathways were sustained by increased uptake of glucose and glutamine, two critical substrates for these cells. Moreover, RS cells showed activation of anabolic processes that resulted in the synthesis of nucleotides and lipids necessary to support their high proliferation. Exposure to drugs targeting PI3K and NF-kB, two master regulators of cellular metabolism, resulted in the shutdown of ATP production and glycolysis. Overall, these data suggest that metabolic rewiring characterizes the transformation of CLL into RS, presenting new translational opportunities.

Dendritic cells (DCs) are versatile professional antigen-presenting cells and play an instrumental role in the generation of antigen-specific T-cell responses. Modulation of DC function holds promise as an effective strategy to improve anti-tumor immunotherapy efficacy and enhance self-antigen tolerance in autoimmune diseases.

Wild-type (WT) and TLR2 knockout (KO) mice at 2 weeks of age were injected intraperitoneally (i.p.) with a single dose of diethylnitrosamine (DEN) to induce hepatocellular carcinoma (HCC). Four weeks later, WT and KO mice were randomly divided into control and treatment groups and treated once every two days for 30 weeks with phosphate buffered saline (PBS) and a mix of 4 TLR2-activating lactic acid-producing probiotics (LAP), respectively. Mice were euthanized after 30 weeks of LAP treatment and their liver tissues were collected for gene expression, histological, flow cytometric and single-cell RNA sequencing analyses.

We demonstrate here that oral administration of a mix of TLR2-activating LAP triggers a marked accumulation of regulatory DCs (rDCs) in the liver of mice. LAP-treated mice are protected from DEN-induced liver injury, fibrosis and HCC in a TLR2-dependent manner. Single-cell transcriptome profiling revealed that LAP treatment determines an immunosuppressive hepatic T-cell program that is characterized by a significantly reduced cytotoxic activity. The observed functional changes of T cells correlated well with the presence of a hepatic DC subset displaying a regulatory or tolerogenic transcriptional signature.

Overall, these data suggest that stimulation of regulatory dendritic cells (rDCs) in the liver by LAP suppresses cytotoxic T-cell function and alleviates DEN-induced liver damage, fibrosis and tumorigenesis.

Intraoperative 13C-glucose infusions in patients with NSCLC show that tumors with high labeling of TCA cycle intermediates progress rapidly, resulting in metastasis and early death. Blocking this pathway suppresses metastasis of human NSCLC cells in mice.

Lactate derived from aerobic glycolysis is crucial for DNA damage repair and chemoresistance. Nevertheless, it is frequently noted that cancer cells depend on glutaminolysis to replenish essential metabolites. Whether and how glutaminolysis might enhance lactate production and facilitate DNA repair in cancer cells remains unknown. Here, it is shown that malate enzyme 2 (ME2), which metabolizes glutamine-derived malate to pyruvate, contributes to lactate production and chemotherapy resistance in ovarian cancer. Mechanistically, chemotherapy reduces the expression of glucose transporters and impairs glucose uptake in cancer cells. The resultant decrease in intracellular glucose levels triggers the acetylation of ME2 at lysine 156 by ACAT1, which in turn potentiates ME2 enzyme activity and facilitates lactate production from glutamine. ME2-derived lactate contributes to the development of acquired chemoresistance in cancer cells subjected to prolonged chemotherapy, primarily by facilitating the lactylation of proteins involved in homologous recombination repair. Targeting ACAT1 to inhibit ME2 acetylation effectively reduced chemoresistance in both in vitro and in vivo models. These findings underscore the significance of acetylated ME2-mediated lactate production from glutamine in chemoresistance, particularly under conditions of reduced intracellular glucose within cancer cell, thereby complementing the Warburg effect and offering new perspectives on the metabolic links to chemotherapy resistance.

Photodynamic therapy (PDT) holds considerable promise as a tumor treatment modality, characterized by its targeted action, compatibility with other therapeutic approaches, and non - invasive features. PDT can achieve remarkable spatiotemporal precision in tumor ablation through the generation of reactive oxygen species (ROS). Nevertheless, despite its potential in tumor treatment, PDT encounters multiple challenges in practical applications. PDT is highly oxygen - dependent, and thus the effectiveness of PDT can be markedly influenced by tumor hypoxia. The co-existence of abnormal vasculature and metabolic deregulation gives rise to a hypoxic microenvironment, which not only sustains tumor survival but also undermines the therapeutic efficacy of PDT. Consequently, targeting tumor angiogenesis and metabolism is essential for revitalizing PDT. This review emphasizes the mechanisms and strategies for revitalizing PDT in tumor treatment, predominantly concentrating on interfering with tumor angiogenesis and reprogramming tumor cell metabolism. Lastly, the outlining future perspectives and current limitations of PDT are also summarized. This could provide new insights and methodologies for overcoming the challenges associated with PDT in tumor treatment, ultimately advancing the field of PDT.

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.

Both exercise and cancer can cause adipose tissue shrinkage. However, only cancer-associated weight loss, namely cachexia, is characterized by profound adipose inflammation and fibrosis. Here, we identified tumor-secreted macrophage migration inhibitory factor (MIF) as a major driver that skews the differentiation of adipose stem and progenitor cells (ASPCs) toward a pro-inflammatory and pro-fibrogenic direction, with reduced adipogenic capacity in cancer cachexia. By contrast, circulating MIF is moderately reduced after exercise. Mechanistically, atypical chemokine receptor 3 (ACKR3) in ASPCs serves as the predominant MIF receptor mediating its pathological effects. Inhibition of MIF by gene ablation in tumor cells or pharmacological blockade, as well as ASPC-specific Ackr3 deficiency, markedly alleviates tumor-induced cachexia. These findings unveil MIF-ACKR3 signaling as a critical link between tumors and cachectic manifestations, providing a promising therapeutic target for cancer cachexia.