Metastatic outgrowth in distant microscopic niches requires sufficient nutrients, including fatty acids (FAs), to support tumor growth and to generate an immunosuppressive tumor microenvironment (TME). However, despite the important role of FAs in metastasis, the regulation of FA supply in metastatic niches has not been defined. In this report, we show that tumor endothelium actively promotes outgrowth and restricts antitumor cytolysis by transferring FAs into developing metastatic tumors. We describe a process of transendothelial FA delivery via endosomes that requires mTORC1 activity. Thus, endothelial cell-specific targeted deletion of Raptor (RptorECKO), a unique component of the mTORC1 complex, significantly reduced metastatic tumor burden that was associated with improved markers of T cell cytotoxicity. Low-dose everolimus that selectively inhibited endothelial mTORC1 improves immune checkpoint responses in metastatic disease models. This work reveals the importance of transendothelial nutrient delivery to the TME, highlighting a future target for therapeutic development.

Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, necessitating the identification of reliable prognostic indicators to enhance treatment outcomes. Recent research has highlighted the triglyceride-glucose (TyG) index as a potential surrogate marker for insulin resistance, which may significantly influence the prognosis of patients undergoing immunotherapy combined with chemotherapy. In this context, the study by Yao et al demonstrates that a high TyG index correlates with improved overall survival and progression-free survival in advanced GC patients receiving sintilimab and chemotherapy. Specifically, patients in the high TyG group had a significantly longer median progression-free survival of 9.8 months [95% confidence interval (CI): 9.2-10.9] compared to 8.0 months (95%CI: 7.5-8.5) in the low TyG group (hazard ratio = 0.58, 95%CI: 0.43-0.79, P < 0.001). Similarly, the median overall survival was significantly longer in the high TyG group at 23.1 months (95%CI: 21.2-NA) vs 16.5 months (95%CI: 13.9-18.3) in the low TyG group (hazard ratio = 0.30, 95%CI: 0.21-0.42, P < 0.001). These findings underscore the strong prognostic potential of the TyG index in guiding treatment strategies for advanced GC. These findings underscore the need for further investigation into the TyG index's role as a prognostic tool and its underlying mechanisms in influencing treatment efficacy. We advocate for additional multicenter studies to validate these results and explore the TyG index's applicability across diverse patient populations, ultimately aiming to refine treatment strategies and improve patient outcomes in advanced GC.

Hepatocellular carcinoma (HCC) resists immunotherapy due to its immunosuppressive microenvironment. Sarcoma homology 2 domain-containing protein tyrosine phosphatase-1 (SHP-1) inhibits T cell receptor signaling, and its pharmacological inhibition is limited by poor selectivity and membrane permeability. Here, we generated CRISPR-edited SHP-1-knockout (KO) CD8+ T cells to enhance adoptive therapy against HCC. Single-cell RNA sequencing of HCC patient T cells revealed elevated SHP-1 in exhausted subsets. SHP-1-KO T cells exhibited increased effector memory T cells (TEM) proportions and enhanced IFN-γ/Granzyme B/perforin secretion, improving cytotoxicity against HCC lines. In humanized PDX models, SHP-1-KO T cells demonstrated superior tumor-killing activity. Transcriptomics identified upregulated lipid metabolism pathways, with HMGCR as a hub gene. Combining SHP-1-KO T cells with simvastatin (HMGCR inhibitor) synergistically amplified anti-HCC efficacy. This study proposes a dual strategy combining SHP-1-targeted cell therapy and metabolic modulation to overcome immunotherapy resistance, offering a translatable approach for HCC treatment.

Osteosarcoma, a highly aggressive malignant bone tumor, is significantly influenced by the intricate interactions within its tumor microenvironment (TME), particularly involving neutrophils. This review delineates the multifaceted roles of neutrophils, including tumor-associated neutrophils (TANs) and neutrophil extracellular traps (NETs), in osteosarcoma's pathogenesis. TANs exhibit both pro- and anti-tumor phenotypes, modulating tumor growth and immune evasion, while NETs facilitate tumor cell adhesion, migration, and immunosuppression. Clinically, neutrophil-related markers such as the neutrophil-to-lymphocyte ratio (NLR) predict patient outcomes, highlighting the potential for neutrophil-targeted therapies. Unraveling these complex interactions is crucial for developing novel treatment strategies that harness the TME to improve osteosarcoma management.

Acute myeloid leukemia (AML) is a heterogeneous blood-related neoplasm that predominantly afflicts older adults with a poor prognosis due to their physical condition and the presence of medical accompanying comorbidities, adverse biological disease features, and suitability for induction intensive chemotherapy and allogenic stem cells transplantation. Recent research into the molecular and biological factors contributing to disease development and progression has led to significant advancements in treatment approaches for older patients with AML. This review article discusses the latest biological and therapeutic developments that are transforming the management of AML in older adults.

Ovarian cancer is a significant global health challenge, with cytoreductive surgery and platinum-based chemotherapy serving as established primary treatments. Unfortunately, most patients relapse and ultimately become platinum-resistant, at which point there are limited effective treatment options. Given the success of immunotherapy in inducing durable treatment responses in several other cancers, its potential in platinum-resistant ovarian cancer (PROC) is currently being investigated. However, in unselected advanced ovarian cancer populations, researchers have reported low response rates to immune checkpoint inhibition, and thus far, no validated biomarkers are predictive of response. Understanding the intricate interplay between platinum resistance, immune recognition, and the tumour microenvironment (TME) is crucial. In this review, we examine the research challenges encountered thus far, the biological rationale for immunotherapy, the underlying mechanisms of immune resistance, and new strategies to overcome resistance.

Recent breakthroughs in cancer immunotherapies have emphasized the importance of harnessing the immune system for treating cancer. Vaccines, which have traditionally been used to promote protective immunity against pathogens, are now being explored as a method to target cancer neoantigens. Over the past few years, extensive preclinical research and more than a hundred clinical trials have been dedicated to investigating various approaches to neoantigen discovery and vaccine formulations, encouraging development of personalized medicine. Nucleic acids (DNA and mRNA) have become particularly promising platform for the development of these cancer immunotherapies. This shift towards nucleic acid-based personalized vaccines has been facilitated by advancements in molecular techniques for identifying neoantigens, antigen prediction methodologies, and the development of new vaccine platforms. Generating these personalized vaccines involves a comprehensive pipeline that includes sequencing of patient tumor samples, data analysis for antigen prediction, and tailored vaccine manufacturing. In this review, we will discuss the various shared and personalized antigens used for cancer vaccine development and introduce strategies for identifying neoantigens through the characterization of gene mutation, transcription, translation and post translational modifications associated with oncogenesis. In addition, we will focus on the most up-to-date nucleic acid vaccine platforms, discuss the limitations of cancer vaccines as well as provide potential solutions, and raise key clinical and technical considerations in vaccine development.

Head and neck cancer (HNC), primarily head and neck squamous cell carcinomas, originates from the squamous epithelium in areas like the oral cavity, lip, larynx, and oropharynx. With high morbidity impacting critical functions, combined treatments like surgery, radiation, and chemotherapy often fall short in advanced stages, highlighting the need for innovative therapies.

This review critically evaluates interleukin (IL) gene therapy for treating HNC. The discussion extends to key ILs in HNC, various gene therapy techniques and delivery methods. We particularly focus on the application of IL-2, IL-12, and IL-24 gene therapies, examining their mechanisms and outcomes in preclinical studies and clinical trials. The final sections address IL gene therapy challenges in HNC, exploring solutions and critically assessing future therapeutic directions.

Despite advancements in genomic and immunotherapy, significant challenges in HNC treatment persist, primarily due to the immunosuppressive nature of the tumor microenvironment and the adverse effects of current therapies. The therapeutic efficacy of IL gene therapy hinges on overcoming these hurdles through refined delivery methods that ensure targeted, tumor-specific gene expression. Future strategies should focus on refining gene delivery methods and combining IL gene therapy with other treatments to optimize efficacy and minimize toxicity.

Head and neck cancer (HNC) is the seventh most common cancer globally, resulting in 440 000 deaths per year. While there have been advancements in chemoradiotherapy and surgery, relapse occurs in more than half of HNCs, and these patients have a median survival of 10 months and a 2-year survival of < 20%. Only a subset of patients displays durable benefits from immunotherapies in metastatic and recurrent HNC, making it critical to understand the tumor microenvironment (TME) underpinning therapy responses in HNC. To recognize biological differences within the TME that may be predictive of immunotherapy response, we applied cutting-edge geospatial whole-transcriptome profiling (NanoString GeoMx Digital Spatial Profiler) and spatial proteomics profiling (Akoya PhenoCycler-Fusion) on a tumor microarray consisting of 25 cores from 12 patients that included 4 immunotherapy-unresponsive (8 cores) and 2 immunotherapy-responsive patients (5 cores), as well as 6 immunotherapy naïve patients (12 cores). Through high-plex, regional-based transcriptomic mapping of the tumor and TME, pathways involved with the complement system and hypoxia were identified to be differentially expressed in patients who went on to experience a poor immunotherapy response. Single-cell, targeted proteomic analysis found that immune cell infiltration of the cancer cell mass and interactions of CD8 T cells with tumor and other immune cells were associated with positive immunotherapy response. The relative abundance of specific tumor phenotypes and their interactions with various immune cells was identified to be different between response groups. This study demonstrates how spatial transcriptomics and proteomics can resolve novel alterations in the TME of HNC that may contribute to therapy sensitivity and resistance.

Patient-derived organoids (PDOs) established from tissues from various tumor types gave the foundation of ex vivo models to screen and/or validate the activity of many cancer drug candidates. Due to their phenotypic and genotypic similarity to the tumor of which they were derived, PDOs offer results that effectively complement those obtained from more complex models. Yet, their potential for predicting sensitivity to combination therapy remains underexplored. In this review, we discuss the use of PDOs in both validation and optimization of multi-drug combinations for personalized treatment strategies in CRC. Moreover, we present recent advancements in enriching PDOs with diverse cell types, enhancing their ability to mimic the complexity of in vivo environments. Finally, we debate how such sophisticated models are narrowing the gap in personalized medicine, particularly through immunotherapy strategies and discuss the challenges and future direction in this promising field.

Cancer is one of the leading causes of death worldwide, and more effective ways of attacking cancer are being sought. Cancer immunotherapy is a new and effective therapeutic method after surgery, radiotherapy, chemotherapy, and targeted therapy. Cancer immunotherapy aims to kill tumor cells by stimulating or rebuilding the body's immune system, with specific efficiency and high safety. However, only few tumor patients respond to immunotherapy and due to the complex and variable characters of cancer immune escape, the behavior and regulatory mechanisms of immune cells need to be deeply explored from more dimensions. Epigenetic modifications, metabolic modulation, and cell-to-cell communication are key factors in immune cell adaptation and response to the complex tumor microenvironment. They collectively determine the state and function of immune cells through modulating gene expression, changing in energy and nutrient demands. In addition, immune cells engage in complex communication networks with other immune components, which are mediated by exosomes, cytokines, and chemokines, and are pivotal in shaping the tumor progression and therapeutic response. Understanding the interactions and combined effects of such multidimensions mechanisms in immune cell modulation is important for revealing the mechanisms of immunotherapy failure and developing new therapeutic targets and strategies.

Cancer heterogeneity remains a significant challenge for effective cancer treatments. Altered energetics is one of the hallmarks of cancer and influences tumor growth and drug resistance. Studies have shown that heterogeneity exists within the metabolic profile of tumors, and personalized-combination therapy with relevant metabolic interventions could improve patient response. Metabolomic studies are identifying novel biomarkers and therapeutic targets that have improved treatment response. The spatial location of elements in the tumor microenvironment are becoming increasingly important for understanding disease progression. The evolution of spatial metabolomics analysis now allows scientists to deeply understand how metabolite distribution contributes to cancer biology. Recently, these techniques have spatially resolved metabolite distribution to a subcellular level. It has been proposed that metabolite mapping could improve patient outcomes by improving precision medicine, enabling earlier diagnosis and intraoperatively identifying tumor margins. This review will discuss how altered metabolic pathways contribute to cancer progression and drug resistance and will explore the current capabilities of spatial metabolomics technologies and how these could be integrated into clinical practice to improve patient outcomes.

Tumor metastasis, the main cause of death in cancer patients, requires outgrowth of tumor cells after their dissemination and residence in microscopic niches. Nutrient sufficiency is a determinant of such outgrowth1. Fatty acids (FA) can be metabolized by cancer cells for their energetic and anabolic needs but impair the cytotoxicity of T cells in the tumor microenvironment (TME)2,3, thereby supporting metastatic progression. However, despite the important role of FA in metastatic outgrowth, the regulation of intratumoral FA is poorly understood. In this report, we show that tumor endothelium actively promotes tumor growth and restricts anti-tumor cytolysis by transferring FA into developing metastatic tumors. This process uses transendothelial fatty acid transport via endosome cargo trafficking in a mechanism that requires mTORC1 activity. Thus, tumor burden was significantly reduced upon endothelial-specific targeted deletion of Raptor, a unique component of the mTORC1 complex (RptorECKO). In vivo trafficking of a fluorescent palmitic acid analog to tumor cells and T cells was reduced in RptorECKO lung metastatic tumors, which correlated with improved markers of T cell cytotoxicity. Combination of anti-PD1 with RAD001/everolimus, at a low dose that selectively inhibits mTORC1 in endothelial cells4, impaired FA uptake in T cells and reduced metastatic disease, corresponding to improved anti-tumor immunity. These findings describe a novel mechanism of transendothelial fatty acid transfer into the TME during metastatic outgrowth and highlight a target for future development of therapeutic strategies.

As one of the most successful human pathogens, Mycobacterium tuberculosis (Mtb) has evolved a diverse array of determinants to subvert host immunity and alter host metabolic patterns. However, the mechanisms of pathogen interference with host metabolism remain poorly understood. Here we show that a glutamine metabolism antagonist, JHU083, inhibits Mtb proliferation in vitro and in vivo. JHU083-treated mice exhibit weight gain, improved survival, a 2.5 log lower lung bacillary burden at 35 days post-infection, and reduced lung pathology. JHU083 treatment also initiates earlier T-cell recruitment, increased proinflammatory myeloid cell infiltration, and a reduced frequency of immunosuppressive myeloid cells when compared to uninfected and rifampin-treated controls. Metabolomic analysis of lungs from JHU083-treated Mtb-infected mice reveals citrulline accumulation, suggesting elevated nitric oxide (NO) synthesis, and lowered levels of quinolinic acid which is derived from the immunosuppressive metabolite kynurenine. JHU083-treated macrophages also produce more NO potentiating their antibacterial activity. When tested in an immunocompromised mouse model of Mtb infection, JHU083 loses its therapeutic efficacy suggesting the drug's host-directed effects are likely to be predominant. Collectively, these data reveal that JHU083-mediated glutamine metabolism inhibition results in dual antibacterial and host-directed activity against tuberculosis.

Alterations in several tripartite motif-containing (TRIM) family proteins have been implicated in the pathogenesis of lung cancer. TRIM28, a member of the TRIM E3 ligase family, has been associated with tumorigenesis, cell proliferation, and inflammation. However, little is known about TRIM28 expression and its role in the immune microenvironment of non-small cell lung cancer (NSCLC).

We assessed the clinical significance of TRIM28 in tissue microarrays and TCGA cohorts. We investigated the function of TRIM28 in syngeneic mouse tumor models, the KrasLSL-G12D/+; Tp53fl/fl (KP) mouse model, and humanized mice. Immune cell composition was analyzed using flow cytometry and immunohistochemistry.

Our findings revealed a positive correlation between TRIM28 expression and the infiltration of suppressive myeloid-derived suppressor cells (MDSCs) in NSCLC. Moreover, silencing TRIM28 enhanced the efficacy of anti-PD-1 immunotherapy by reshaping the inflamed tumor microenvironment. Mechanistically, we demonstrated that TRIM28 could physically interact with receptor-interacting protein kinase 1 (RIPK1) and promote K63-linked ubiquitination of RIPK1, which is crucial for sustaining activation of the NF-κB pathway. Mutagenesis of the E3 ligase domain corroborated the essential role of E3 ligase activity in TRIM28-mediated NF-κB activation. Further experiments revealed that TRIM28 could upregulate the expression of CXCL1 by activating NF-κB signaling. CXCL1 could bind to CXCR2 on MDSCs and promote their migration to the tumor microenvironment. TRIM28 knockdown increased responsiveness to anti-PD-1 therapy in immunocompetent mice, characterized by increased CD8+T tumor-infiltrating lymphocytes and decreased MDSCs.

The present study identified TRIM28 as a promoter of chemokine-driven recruitment of MDSCs through RIPK1-mediated NF-κB activation, leading to the suppression of infiltrating activated CD8+T cells and the development of anti-PD-1 resistance. Understanding the regulation of MDSC recruitment and function by TRIM28 provides crucial insights into the association between TRIM28 signaling and the development of an immunosuppressive tumor microenvironment. These insights may inform the development of combination therapies to enhance the effectiveness of immune checkpoint blockade therapy in NSCLC.

As a result of metabolic reprogramming, cancer cells display high rates of glycolysis, causing an excess production of lactate along with an increase in extracellular acidity. Proton-linked monocarboxylate transporters (MCTs) are crucial in the maintenance of this metabolic phenotype, by mediating the proton-coupled lactate flux across cell membranes, also contributing to cancer cell pH regulation. Among the proteins codified by the SLC16 gene family, MCT1 and MCT4 isoforms are the most explored in cancers, being overexpressed in many cancer types, from solid tumours to haematological malignancies. Similarly to what occurs in particular physiological settings, MCT1 and MCT4 are able to mediate lactate shuttles among cancer cells, and also between cancer and stromal cells in the tumour microenvironment. This form of metabolic cooperation is responsible for important cancer aggressiveness features, such as cell proliferation, survival, angiogenesis, migration, invasion, metastasis, immune tolerance and therapy resistance. The growing understanding of MCT functions and regulation is offering a new path to the design of novel inhibitors that can be foreseen in clinical practices. This review provides an overview of the role of MCT isoforms in cancer and summarizes the recent advances in their pharmacological targeting, highlighting the potential of new potent and selective MCT1 and/or MCT4 inhibitors in cancer therapeutics, and anticipating its inclusion in clinical practice.

Immunotherapy has revolutionized cancer treatment and revitalized efforts to harness the power of the immune system to combat a variety of cancer types more effectively. However, low clinical response rates and differences in outcomes due to variations in the immune landscape among patients with cancer continue to be major limitations to immunotherapy. Recent efforts to improve responses to immunotherapy have focused on targeting cellular metabolism, as the metabolic characteristics of cancer cells can directly influence the activity and metabolism of immune cells, particularly T cells. Although the metabolic pathways of various cancer cells and T cells have been extensively reviewed, the intersections among these pathways, and their potential use as targets for improving responses to immune-checkpoint blockade therapies, are not completely understood. This review focuses on the interplay between tumor metabolites and T-cell dysfunction as well as the relationship between several T-cell metabolic patterns and T-cell activity/function in tumor immunology. Understanding these relationships could offer new avenues for improving responses to immunotherapy on a metabolic basis.

As an essential regulator of type I interferon (IFN) response, TMEM173 participates in immune regulation and cell death induction. In recent studies, activation of TMEM173 has been regarded as a promising strategy for cancer immunotherapy. However, transcriptomic features of TMEM173 in B-cell acute lymphoblastic leukemia (B-ALL) remain elusive.

Quantitative real-time PCR (qRT-PCR) and western blotting (WB) were applied to determine the mRNA and protein levels of TMEM173 in peripheral blood mononuclear cells (PBMCs). TMEM173 mutation status was assessed by Sanger sequencing. Single-cell RNA sequencing (scRNA-seq) analysis was performed to explore the expression of TMEM173 in different types of bone marrow (BM) cells.

The mRNA and protein levels of TMEM173 were increased in PBMCs from B-ALL patients. Besides, frameshift mutation was presented in TMEM173 sequences of 2 B-ALL patients. ScRNA-seq analysis identified the specific transcriptome profiles of TMEM173 in the BM of high-risk B-ALL patients. Specifically, expression levels of TMEM173 in granulocytes, progenitor cells, mast cells, and plasmacytoid dendritic cells (pDCs) were higher than that in B cells, T cells, natural killer (NK) cells, and dendritic cells (DCs). Subset analysis further revealed that TMEM173 and pyroptosis effector gasdermin D (GSDMD) restrained in precursor-B (pre-B) cells with proliferative features, which expressed nuclear factor kappa-B (NF-κB), CD19, and Bruton's tyrosine kinase (BTK) during the progression of B-ALL. In addition, TMEM173 was associated with the functional activation of NK cells and DCs in B-ALL.

Our findings provide insights into the transcriptomic features of TMEM173 in the BM of high-risk B-ALL patients. Targeted activation of TMEM173 in specific cells might provide new therapeutic strategies for B-ALL patients.

As one of the most successful human pathogens, Mycobacterium tuberculosis (Mtb) has evolved a diverse array of determinants to subvert host immunity and alter host metabolic patterns. However, the mechanisms of pathogen interference with host metabolism remain poorly understood. Here we show that a novel glutamine metabolism antagonist, JHU083, inhibits Mtb proliferation in vitro and in vivo. JHU083-treated mice exhibit weight gain, improved survival, a 2.5 log lower lung bacillary burden at 35 days post-infection, and reduced lung pathology. JHU083 treatment also initiates earlier T-cell recruitment, increased proinflammatory myeloid cell infiltration, and a reduced frequency of immunosuppressive myeloid cells when compared to uninfected and rifampin-treated controls. Metabolomics analysis of lungs from JHU083-treated Mtb-infected mice revealed reduced glutamine levels, citrulline accumulation suggesting elevated NOS activity, and lowered levels of quinolinic acid which is derived from the immunosuppressive metabolite kynurenine. When tested in an immunocompromised mouse model of Mtb infection, JHU083 lost its therapeutic efficacy suggesting the drug's host-directed effects are likely to be predominant. Collectively, these data reveal that JHU083-mediated glutamine metabolism inhibition results in dual antibacterial and host-directed activity against tuberculosis.

As a malignant digestive system tumor, pancreatic cancer has unique metabolic characteristics. In recent years, the study of pancreatic cancer metabolism is in full swing, which provides a new direction for the treatment of pancreatic cancer patients. However, there is no systematic report of pancreatic cancer metabolism. In this paper, bibliometrics and visualization methods were used to analyze the number of publications, countries/regions, authors, institutions, journals, co-cited references, and keywords of pancreatic cancer metabolism articles, to summarize the research trends and predict research hotspots.

We searched, screened and downloaded articles on pancreatic cancer metabolism through the Web of Science Core Collection (WoSCC). Using CiteSpace, VOSviewer and Bibliometrix Package to analyze publications, countries/regions, authors, institutions, journals, co-cited references, and keywords of pancreatic cancer metabolism to identify research trends and predict research hotspots.

According to the inclusion and exclusion criteria, a total of 5,255 articles were retrieved during the period 1943-2022. The number of publications on pancreatic cancer metabolism is increasing year by year. The United States (n=1602, 30.49%), China (n=1074, 20.44%), and Italy (n=313, 5.96%) are the three countries with the largest number of publications and citations, and there is close cooperation between countries. LI J (n=55) is the most prolific author. FUDAN UNIV (n=348) is the most published institution. CANCERS (n=118), PLOS ONE (n=93), and CANCER RESEARCH (n=80) are the most popular journals in this field. "Nutriment-deficient environment", "cancer chemoprevention" and "targeting cancer stem cell" are the main areas of focus. "immunotherapy", "ferroptosis" and "targeted therapy" are hot keywords in recent years. Taking pancreatic cancer metabolism as an entry point to study the role of traditional Chinese medicine (TCM) mainly focuses on curcumin and resveratrol, lack of broader and deeper research on TCM.

The number of publications on pancreatic cancer metabolism has generally increased, and scholars have generally paid more attention to this field. "immunotherapy", "ferroptosis" and "targeted therapy" are the current research hotspots. The in-depth study of pancreatic cancer metabolism will provide new ideas for the treatment of pancreatic cancer.

As a common cancer-related death worldwide, pancreatic adenocarcinoma (PAAD) has significantly increased mortality in recent years. In recent years, tumor mutation burden (TMB) has been regarded as the most popular biomarker for PAAD immunotherapy. However, it remains unclear which gene mutations affect TMB and immune response in pancreatic adenocarcinoma.

The somatic mutation images of PAAD samples were downloaded from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC). Based on the expression data of the TCGA and IGCC cohorts, various bioinformatics algorithms are used for evaluating the prognostic value and functional annotation of some frequently somatically mutated genes. Furthermore, the correlation between gene mutation and tumor immunity was also evaluated.

The results showed that lysine methyltransferase 2C (KMT2C) and paternally expressed 3 (PEG3) are frequently mutated genes in PAAD. Patients with KMT2C and PEG3 mutations have higher TMB severity and a lousy prognosis. In addition, the mutations of KMT2C and PEG3 genes positively regulate the metabolic and protein-related pathways in PAAD. Meanwhile, significant differences in the composition of the immune cells were observed for KMT2C and PEG3 mutations PAAD patients, for providing additional guidelines for antitumor treatments in various KMT2C and PEG3 mutation states in PAAD.

This study reveals that KMT2C and PEG3 mutation may serve as biomarkers for predicting prognosis and guiding anti-PAAD immunotherapy for PAAD patients.

Accumulated oncometabolites in the tumor microenvironment (TME) suppresses the metabolism, expansion, and function of T cells. Immunosuppressive TME also impeded Chimeric Antigen Receptor (CAR)-T cells mediated cytotoxicity since CAR-T cells had to adapt the in vivo metabolic characteristics with high levels of oncometabolites. We screened oncometabolites for the inhibition of glucose uptake in CD8 + T cells and found Kynurenine (Kyn) showed the strongest inhibiting effect on glucose uptake. In vitro experiments showed that 120 μM Kyn treatment in CD8 + T cells resulted in inhibiting the expansion of CD8 + T cells, decreasing the production of granzyme B and interferon-γ. CAR-T cells mediated cytotoxicity was also impaired by the high Kyn treatment from killing assay. We then explored the anti-tumor effect of Kynureninase (KYNU) modified CAR-T cells through catabolism o oncometabolites Kyn. KYNU over-expression (OE) CAR-T cells showed a superior killing effect against cancer cells even in the immunosuppressive TME with high Kyn levels. In vivo experiments confirmed KYNU-OE CAR-T cells showed an excellent anti-tumor effect in a TME with high Kyn levels since it improved the survival of mice bearing NALM6 cancer cells and NALM6-IDO1 cancer cells. The KYNU-modified CAR-T cells displayed distinct phenotypes related to the expansion, function, and memory differentiation status of CAR-T cells. This study explores an immunotherapy strategy for patients with alterations in Kyn metabolism. KYNU-OE CAR-T cells take advantage of Kyn catabolism to improve anti-tumor activity in the metabolic immunosuppressive TME with high Kyn.

Prostate cancer (PCa) is a common malignancy that poses a major threat to the health of men. Prostate-specific antigen (PSA) and its derivatives, as FDA-approved detection assays, are insufficient to serve as optimal markers for patient prognosis and clinical decision-making. It is widely acknowledged that aberrant glycolytic metabolism in PCa is related to tumor progression and acidifies the tumor microenvironment (TME). Considering the non-negligible impacts of glycolysis and immune functions on PCa, we developed a combined classifier in prostate cancer. The Glycolysis Score containing 19 genes and TME Score including three immune cells were created, using the univariate and multivariate Cox proportional hazards model, log-rank test, least absolute shrinkage and selection operator (LASSO) regression analysis and the bootstrap approach. Combining the glycolysis and immunological landscape, the Glycolysis-TME Classifier was then constructed. It was observed that the classifier was more accurate in predicting the prognosis of patients than the current biomarkers. Notably, there were significant differences in metabolic activity, signaling pathways, mutational landscape, immunotherapeutic response, and drug sensitivity among the Glycolysis^high/TME^low, Mixed group and Glycolysis^low/TME^high identified by this classifier. Overall, due to the significant prognostic value and potential therapeutic guidance of the Glycolysis-TME Classifier, we anticipate that this classifier will be clinically beneficial in the management of patients with PCa.

Tumor metabolism supports the energetic and biosynthetic needs of rapidly proliferating cancer cells and modifies intra- and intercellular signaling to enhance cancer cell invasion, metastasis, and immune evasion. Prostate cancer exhibits unique metabolism with high rates of de novo fatty acid synthesis driven by activation of the androgen receptor (AR). Increasing evidence suggests that activation of this pathway is functionally important to promote prostate cancer aggressiveness. However, the mechanisms by which fatty acid synthesis are beneficial to prostate cancer have not been well defined. In this review, we summarize evidence indicating that fatty acid synthesis drives progression of prostate cancer. We also explore explanations for this phenomenon and discuss future directions for targeting this pathway for patient benefit.