Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease which remains poorly understood. Increasing evidence suggests that the aryl hydrocarbon receptor (AHR) plays a role in the pathogenesis of several cancers; however, its role in PDAC is unclear because AHR exhibits both pro- and anti-tumor activities. Here we evaluated the role of AHR in CR705 and K8484 murine PDAC cells in vitro and CR705 cells in vivo. Loss of Ahr did not affect cell proliferation compared with Cas9 control cells and no differences in tumor development between CR705Cas9 and CR705AhrKO cells were observed in immunocompromised mice. Conversely, tumors from CR705AhrKO cells grew more slowly than tumors from CR705Cas9 cells in immune competent mice. RNA sequencing identified 1279 genes upregulated and 586 genes downregulated in CR705AhrKO tumors compared with CR705Cas9 tumors. Pathway analysis identified immunoregulatory interactions, interferon signaling, and chemokine signaling among the top upregulated pathways. Increased infiltration of CD45+ cells and higher numbers of CD8+ T cells and F4/80+ cells were observed in CR705AhrKO tumors. Ahr deficiency in macrophages (LysMCre) or lymphocytes (RorcCre) did not alter tumor development of CR705Cas9 cells compared with Ahrfl/fl mice. CR705AhrKO tumors in RorcCre mice, but not in LysMCre mice had significantly lower tumor weights normalized to body weights compared with CR705AhrKO tumors in WT mice. These findings show that Ahr loss in CR705 pancreatic cancer cells is sufficient to induce proinflammatory gene responses that contribute to increased immune cell infiltration and reduced tumor growth.

Glioblastoma (GBM) is the most aggressive primary brain tumor exhibiting extensive immune evasion mechanisms that hinder effective therapeutic interventions. This narrative review explores the immunomodulatory pathways contributing to tumor escape in GBM, specifically focusing on the role of Tryptophan (TRP) metabolism and its downstream mediators Tryptophan metabolism through the kynurenine pathway (KP) is initiated by indoleamine 2,3-dioxygenase (IDO) and tryptophan-2,3-dioxygenase (TDO2) enzymes and serves as a crucial mechanism for promoting an immunosuppressive microenvironments and systemic immunotolerance. Emerging evidence also indicates a non-enzymatic role for IDO1 signaling in these processes. The downstream effectors interact with immune cells, inducing local immunosuppression within the tumor microenvironment and altering peripheral immune responses.

We systematically reviewed databases (MEDLINE via PubMed, Science Direct, and Embase) through October 2024 to highlight the interplay between local immune escape mechanisms and circulating immunotolerance, emphasizing the role of TRP metabolic enzymes in supporting GBM progression.

The literature review identified 99 records. TRP-related mechanisms play a central role in fostering immunotolerance in GBM. These phenomena involve intricate interactions between the infiltrating and circulating myeloid and lymphoid compartments, ultimately shaping a tolerant, pro-tumoral environment and the peripheral immunophenotype.

The biological activity of IDO1 and TRP metabolites positions these compounds as potential markers of disease activity and promising molecular targets for future therapeutic approaches.

As found in human lung squamous cell carcinoma (LUSC), STING1 involved in ER-Golgi intermediate compartment (ERGIC) could coordinate immune responses to ectopic DNA triggered by DNA-targeted chemotherapy. ERGIC STING1 is considered to compete with nuclear STING1 to decline aryl hydrocarbon receptor (AhR)-chromosomal instability (CIN)-triggered chronic STING activation which could cause therapeutic resistance. Moreover, GSTP1 was proved to inhibit ERGIC-STING1 via promoting S-glutathione modification of STING1. Hence, a potent GSTP1-targeted Pt(IV) hybrid NBDHEX-DN604, was designed via conjugating a GSTP1 inhibitor NBDHEX to the axial position of Pt(IV) prodrug. As mentioned, hypoxia is mainly observed in malignant tumors and develops acquired drug resistance. In vitro bio-properties of hypoxic SK-MES-1/cDDP cells demonstrated that NBDHEX-DN604 could reverse chemo-immuno resistance via intercepting GSTP1 to activate ERGIC STING1, leading to the decrease of nuclear STING1. The mechanistic data indicated that NBDHEX-DN604 could elevate ERGIC STING1 to mitigate nuclear STING1-mediated AhR-TLS-CIN-chronic activation. Meanwhile, NBDHEX-DN604 was found to decline STING1-AhR-CIN to circumvent chemo-immuno resistance, resulting in predominant in vivo antitumor effect in HY-KLN-205/cDDP-inoculated BALB/c mice. The data provide a novel rationale for the mixed chemo-immunotherapy of NBDHEX-DN604 as a potent Pt(IV) therapeutic method for patients with resistant LUSC.

Tumor subclones refer to distinct cell populations within the same tumor that possess different genetic characteristics. They play a crucial role in understanding tumor heterogeneity, evolution, and therapeutic resistance. The formation of tumor subclones is driven by several key mechanisms, including the inherent genetic instability of tumor cells, which facilitates the accumulation of novel mutations; selective pressures from the tumor microenvironment and therapeutic interventions, which promote the expansion of certain subclones; and epigenetic modifications, such as DNA methylation and histone modifications, which alter gene expression patterns. Major methodologies for studying tumor subclones include single-cell sequencing, liquid biopsy, and spatial transcriptomics, which provide insights into clonal architecture and dynamic evolution. Beyond their direct involvement in tumor growth and invasion, subclones significantly contribute to tumor heterogeneity, immune evasion, and treatment resistance. Thus, an in-depth investigation of tumor subclones not only aids in guiding personalized precision therapy, overcoming drug resistance, and identifying novel therapeutic targets, but also enhances our ability to predict recurrence and metastasis risks while elucidating the mechanisms underlying tumor heterogeneity. The integration of artificial intelligence, big data analytics, and multi-omics technologies is expected to further advance research in tumor subclones, paving the way for novel strategies in cancer diagnosis and treatment. This review aims to provide a comprehensive overview of tumor subclone formation mechanisms, evolutionary models, analytical methods, and clinical implications, offering insights into precision oncology and future translational research.

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor originally identified as the target mediating the toxic effects of environmental pollutants including polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs) and dioxins. For years, AHR activation was actively avoided during drug development. However, the AHR was later identified as an important physiological regulator of the immune response. These findings triggered a paradigm shift that resulted in identification of the AHR as a regulator of both innate and adaptive immunity and outlined a pathway for its modulation by the diet, commensal flora and metabolism in the context of autoimmunity, cancer and infection. Moreover, the AHR was revealed as a candidate target for the therapeutic modulation of the immune response. Indeed, the first AHR-activating drug (tapinarof) was recently approved for the treatment of psoriasis. Clinical trials are underway to evaluate the effects of tapinarof and other AHR-targeting therapeutics in inflammatory diseases, cancer and infections. This Review outlines the molecular mechanism of AHR action, and describes how it regulates the immune response. We also discuss links to disease and AHR-targeting therapeutics that have been tested in past and ongoing clinical trials.

Kynurenic acid (KYNA) is one of the metabolites of tryptophan (Trp), which can be supplied by endogenous synthesis or diet and involves various aspects of nutrition and metabolism. KYNA has been proven to be an antagonist of α7-nicotinic acetylcholine and NMDA receptors, which can regulate the neurotransmission of cholinergic and glutaminergic acid, so KYNA is mainly associated with neurodegenerative diseases. Other metabolites in the Trp and kynurenine metabolic pathways, such as 3-hydroxy-l-kynurenine (3-HK), 5-hydroxytryptophan (5-HT), and quinolinic acid (QA), are also involved in immune regulation and have pro-stimulatory or anti-excitatory toxicity. KYNA is present in both the human body and the daily diet, so it has the potential as a new dietary supplement. It may be of great significance in treating psychiatric disorders.

OCT4 (Octamer-binding transcription factor 4, encoded by the POU5F1 gene) is a master transcription factor for maintaining the self-renewal and pluripotency of pluripotent stem cells, as well as a pioneer factor regulating epigenetics-driven cell reprogramming and cell fate conversion. It is also detected in a variety of cancer tissues and particularly in a small subpopulation of cancer cells known as cancer stem cells (CSCs). Accumulating evidence has revealed that CSCs are a dynamic population, exhibiting shift between multipotency and differentiation states, or quiescence and proliferation states. Such cellular plasticity of CSCs is profoundly influenced by dynamic interplay between CSCs and the tumor microenvironment (TME). Here, we review recent evidence showing that OCT4 expressed in CSCs plays a multifaceted role in shaping the TME by interacting with the cellular TME components, including cancer-associated fibroblasts, tumor endothelial cells, tumor-infiltrating immune cells, as well as the non-cellular TME components, such as extracellular matrix (ECM), metabolites, soluble factors (e.g., growth factors, cytokines and chemokines), and intra-tumoral microbiota. Together, OCT4 regulates crucial processes encompassing ECM remodeling, epithelial-mesenchymal transition, metabolic reprogramming, angiogenesis, and immune responses. The complex and bidirectional interactions between OCT4-expressing CSCs and the TME create a supportive niche for tumor growth, invasion, and resistance to therapy. Better understanding OCT4's roles in such interactions can provide deeper insights into potential therapeutic strategies and targets for disrupting the supportive environment of tumors. The emerging therapies targeting OCT4 in CSCs might hold promise to resensitize therapeutic-resistant cancer cells, and to eradicate all cancer cells when combined with other therapies targeting the bulk of differentiated cancer cells as well as the TME.

Diet impacts cancer in diverse manners. Multiple nutritional effects on tumors are mediated by dietary modulation of commensals, residing in mucosal surfaces and possibly also within the tumor microenvironment. Mechanistically understanding such diet-microbiome-host interactions may enable to develop precision nutritional interventions impacting cancer development, dissemination, and treatment responses. However, data-driven nutritional strategies integrating diet-microbiome interactions are infrequently incorporated into cancer prevention and treatment schemes. Herein, we discuss how dietary composition affects cancer-related processes through alterations exerted by specific nutrients and complex foods on the microbiome. We highlight how dietary timing, including time-restricted feeding, impacts microbial function in modulating cancer and its therapy. We review existing and experimental nutritional approaches aimed at enhancing microbiome-mediated cancer treatment responsiveness while minimizing adverse effects, and address challenges and prospects in integrating diet-microbiome interactions into precision oncology. Collectively, mechanistically understanding diet-microbiome-host interactomes may enable to achieve a personalized and microbiome-informed optimization of nutritional cancer interventions.

Approximately 77.4% of uterine leiomyomas carry MED12 gene mutations (mut-MED12), which are specifically associated with strikingly upregulated expression and activity of the tryptophan 2,3-dioxygenase (TDO2) enzyme, leading to increased conversion of tryptophan to kynureine. Kynurenine increases leiomyoma cell survival by activating the aryl hydrocarbon receptor (AHR). We used a leiomyoma-relevant model, in which a MED12 Gly44 mutation was knocked in by CRISPR in a human uterine myometrial smooth muscle (UtSM) cell line, in addition to primary leiomyoma cells from 26 patients to ascertain the mechanisms responsible for therapeutic effects of apigenin, a natural compound. Apigenin treatment significantly decreased cell viability, inhibited cell cycle progression, and induced apoptosis preferentially in mut-MED12 versus wild-type primary leiomyoma and UtSM cells. Apigenin not only blocked AHR action but also decreased TDO2 expression and kynurenine production, preferentially in mut-MED12 cells. Apigenin did not alter TDO2 enzyme activity. TNF and IL-1β, cytokines upregulated in leiomyoma, strikingly induced TDO2 expression levels via activating the NF-κB and JNK pathways, which were abolished by apigenin. Apigenin or a TDO2 inhibitor decreased UtSM cell viability induced by TNF/IL-1β. We provide proof-of-principle evidence that apigenin is a potential therapeutic agent for mut-MED12 leiomyomas.

The role of tryptophan 2,3-dioxygenase2 (TDO2), a key enzyme in the L-tryptophan (Trp)-kynurenine (Kyn) pathway, in liver transplant immunity is unclear. This study aims to explore the role of TDO2 in liver transplant rejection.

We used clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 to construct a TDO2 knockout rat model for liver transplant rejection. We validated the effects of TDO2 on acute rejection and survival, assessed TDO2 expression, and measured Trp and Kyn levels. We studied how TDO2 deficiency affects inflammatory cytokines, analyzed immune cell subtypes and their spatial distribution, and examined programmed death 1 and programmed cell death-ligand 1 (PDL1) spatial distribution and expression using multiplex immunohistochemistry. We also validated the regulatory mechanism of TDO2 on transplant-related immune cells in vivo and in vitro.

TDO2 deficiency in the allograft liver worsens acute rejection and reduces survival rates. During transplant rejection, TDO2 expression increases, enhancing Trp metabolism and elevating serum Kyn levels. TDO2 knockout mitigates this process. The TDO2-Kyn-aryl hydrocarbon receptor pathway regulates acute rejection. TDO2 knockout reprograms immune cell distribution, decreasing regulatory T cells and M2 macrophages in the intermediate region while increasing CD8+ T cells and M1 macrophages in the portal area, leading to M1 polarization. Additionally, TDO2 deficiency raises programmed death 1 and programmed cell death-ligand 1 expression, varying with the spatial distribution and quantity of immune cells. TDO2 can regulate the proliferation and differentiation of various immune cells through the Kyn-aryl hydrocarbon receptor pathway.

Collectively, we elucidated the mechanism of TDO2 in liver transplant immune rejection and used spatial immunity to reveal the impact of TDO2 on liver transplantation.

Tryptophan catabolism is implicated in the progression of cardiovascular disease. We sought to investigate the prognostic value of tryptophan catabolism-related features in patients with acute myocardial infarction (AMI).

A prospective cohort of 4071 patients (mean age: 60.7 years; 69.1 % men) with AMI between February 2017 and June 2019 was included and followed up for a median of 5.6 years (IQR 5.1-6.2). There were 666 all-cause deaths, 365 cardiovascular deaths, and 559 HF events. Plasma levels of tryptophan-related metabolites were measured using liquid chromatography tandem mass spectrometry (LC-MS/MS), and were repeatedly determined in 1044 patients after discharge. Tryptophan, kynurenine, indole-3-propionic acid, and indole-3-lactic acid were screened to construct tryptophan metabolites combination (TMC) score using coefficients from predictive models for MACE. Patients were divided into 3 groups by TMC tertiles. Patients with higher TMC score were older, more likely to be male and have hypertension. Compared to those with TMC tertile 1, patients in TMC tertile 3 had significant associations with the risk of all-cause death (HR: 1.90; 95 %CI: 1.54-2.34), cardiovascular death (HR: 2.32; 95 %CI: 1.71-3.15) and incident HF (HR: 1.77; 95 %CI: 1.40-2.24). The incremental prognostic value of TMC score over the Grace score was measured by the likelihood ratio, C-statistic, continuous net reclassification improvement (NRI), and integrated discrimination improvement (IDI) for prediction, discrimination, and reclassification of outcomes.

In this hospital-based AMI cohort, the TMC score was significantly associated with all-cause mortality, cardiovascular mortality, and incident HF, and improved risk stratification beyond established clinical risk factors. The TMC score provided a novel tool for assessment of Trp catabolism dysfunction and outcomes risk.

Colon cancer (CC) remains a primary contributor to cancer-related fatalities worldwide, driven by difficulties in early diagnosis and constrained therapeutic options. Recent studies underscore the importance of the tumor microenvironment (TME), notably tumor-associated macrophages (TAMs), in fostering malignancy progression and therapy resistance. Through their inherent plasticity, TAMs facilitate immunosuppression, angiogenic processes, metastatic spread, and drug tolerance. In contrast to M1 macrophages, which promote inflammatory and tumoricidal responses, M2 macrophages support tumor expansion and dissemination by exerting immunosuppressive and pro-angiogenic influences. Consequently, manipulating TAMs has emerged as a potential avenue to enhance treatment effectiveness. This review outlines the origins, polarization states, and functions of TAMs in CC, highlights their role in driving tumor advancement, and surveys ongoing efforts to target these cells for better patient outcomes. Emerging therapeutic strategies aimed at modulating TAM functions - including depletion strategies, reprogramming approaches that shift M2-polarized TAMs toward an M1 phenotype, and inhibition of key signaling pathways sustaining TAM-mediated immunosuppression-are currently under active investigation. These approaches hold promise in overcoming TAM - induced resistance and improving immunotherapeutic efficacy in CC.

Glioblastoma (GBM) is a highly aggressive brain tumor characterized by rapid cell proliferation, invasive behavior, and chemoresistance. The aryl hydrocarbon receptor (AhR) is implicated in chemoresistance and immune evasion, making it a promising therapeutic target. Natural compounds such as flavonoids have gained attention for their anti-inflammatory, antioxidant, and anticancer properties. Among them, naringenin, a citrus-derived flavonoid, exerts antiproliferative, pro-apoptotic, and immunomodulatory effects.

This study investigated the antiglioma effects of the flavonoid naringenin on the viability, growth, and migration of glioma cells and its potential role as an AhR modulator.

Human (U87) and rat (C6) glioma cell lines were exposed to naringenin (10-300 µM) alone or in combination with the AhR agonist indole-3-carbinol (50 µM) for 24 to 48 h. Cell viability, scratch wound, and cell migration assays were performed. The expression of inflammatory markers was also analyzed by RT-qPCR.

Naringenin exerted dose- and time-dependent inhibition of cell viability and migration. The treatment decreased the gene expression of interleukin-6 (IL-6) and chemokine (CCL2), alongside increased tumor necrosis factor-alpha (TNF-α) expression, an effect reversed by the AhR agonist.

These findings highlight naringenin's potential as an antiglioma agent and its role in AhR signaling.

Myrobalan fruits are important ingredients of traditional remedies, such as the Ayurvedic formulation Triphala or the Tibetan formulation Bras bu 3. Myrobalan-containing remedies are described to have positive effects on metabolism, the cardiovascular system, and the immune system. The chemical composition of botanical mixtures can be very complex, and it is often impossible to identify individual compounds as specific active ingredients, which suggests a multi-target mode of action. In this in vitro study, the effect of myrobalan extracts in human cell models was investigated to gain more information about the molecular mechanism of action and to find possible synergistic effects. Direct and indirect antioxidant effects were investigated, and the activation of immunobiochemical metabolic pathways involved in the cellular immune response was examined in cell lines treated with extracts of the fruits of Phyllanthus emblica, Terminalia chebula and Terminalia bellirica, as well as a combination of them. In particular, a synergistic effect on the activation of the endogenous antioxidant defence system was observed with the combined treatment of the three fruit extracts. An integrated transcriptome analysis of cells treated with a combination of fruit extracts confirmed an effect on immune pathways, oxidative stress, and detoxification processes. This study shows the modulation of various signalling pathways and cellular processes that may be part of the multi-target mechanism of individual and combined myrobalan fruit extracts. Although the results are limited to in vitro data, they contribute to a better understanding of how botanical mixtures work and provide hypotheses for further research.

Anti-tumor immunity, including innate and adaptive immunity is critical in inhibiting tumorigenesis and development of tumor. The adaptive immunity needs specific lymph organs such as tertiary lymphoid structures (TLSs), which are highly correlated with improved survival outcomes in many cancers. In recent years, with increasing attention on the TLS in tumor microenvironment, TLSs have emerged as a novel target for anti-tumor therapy. Excitingly, studies have shown the contribution of TLSs to the adaptive immune responses. However, it is unclear how TLSs to form and how to more effectively defense against tumor through TLS formation. Recent studies have shown that the inflammation plays a critical role in TLS formation. Interestingly, studies have also found that gut microbiota can regulate the occurrence and development of inflammation. Therefore, we here summarize the potential effects of gut microbiota- mediated inflammation or immunosuppression on the TLS formation in tumor environments. Meanwhile, this review also explores how to manipulate mature TLS formation through regulating gut microbiota/metabolites or gut microbiota associated signal pathways for anti-tumor immunity, which potentially lead to a next-generation cancer immunotherapy.

While immunotherapy has shown some efficacy in lung adenocarcinoma (LUAD) patients, many respond only partially or not at all. One limitation in improving outcomes is the lack of a complete understanding of immune checkpoint regulation. Here, we investigated a possible link between an environmental chemical receptor implicated in lung cancer and immune regulation, the AhR, a known but counterintuitive mediator of immunosuppression (interferon (IFN)-γ), and regulation of two immune checkpoints (PD-L1 and IDO). AhR gene-edited LUAD cell lines, a syngeneic LUAD mouse model, bulk and scRNA sequencing of LUADs and tumor-infiltrating T cells were used to map out a signaling pathway leading from IFN-γ through the AhR to JAK/STAT, PD-L1, IDO, and tumor-mediated immunosuppression. The data demonstrate that: (1) IFN-γ activation of the JAK/STAT pathway leading to PD-L1 and IDO1 up-regulation is mediated by the AhR in murine and human LUAD cells, (2) AhR-driven IDO1 induction results in the production of Kynurenine (Kyn), an AhR ligand, which likely mediates an AhR→IDO1→Kyn→AhR amplification loop, (3) transplantation of AhR-knockout LUAD cells results in long-term tumor immunity in most recipients. (4) The 23% of AhR-knockout tumors that do grow do so at a much slower pace than controls and exhibit higher densities of CD8+ T cells expressing markers of immunocompetence, increased activity, and increased cell-cell communication. The data definitively link the AhR to IFN-γ-induced JAK/STAT pathway and immune checkpoint-mediated immunosuppression and support the targeting of the AhR in the context of LUAD.

Host-microorganism encounters take place in many different ways and with different types of outcomes. Three major types of microorganisms need to be distinguished: (1) pathogens that cause harm to the host and must be controlled; (2) environmental microorganisms that can be ignored but must be controlled at higher abundance; and (3) symbiotic microbiota that require support by the host. Recent evidence indicates that the aryl hydrocarbon receptor (AHR) senses and initiates signalling and gene expression in response to a plethora of microorganisms and infectious conditions. It was originally identified as a receptor that binds xenobiotics. However, it was subsequently found to have a critical role in numerous biological processes, including immunity and inflammation and was recently classified as a pattern recognition receptor. Here we review the role of the AHR in host-pathogen interactions, focusing on AHR sensing of different microbial classes, the ligands involved, responses elicited and disease outcomes. Moreover, we explore the therapeutic potential of targeting the AHR in the context of infection.

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.

ASS1(argininosuccinate synthase 1) is a rate-limiting enzyme in the urea cycle, catalyzing the synthesis of argininosuccinate from citrulline and aspartate to ultimately produce arginine and support cellular metabolism. Increasing evidence suggests that ASS1 is commonly dysregulated in the tumor microenvironment, promoting tumor cell metastasis and infiltration. With a deeper understanding of tumor metabolic reprogramming in recent years, the impact of ASS1 dysregulation on abnormal tumor metabolism has attracted growing interest among researchers. In tumors with lacked or downregulated expression of ASS1, tumor cells become 'addicted' to exogenous arginine. Several strategies for arginine deprivation have been developed and entered clinical trials for treating such tumors. Therefore, we focus on elucidating the commonalities and characteristics of ASS1 dysregulation in tumors, as well as its implications for diagnosis, treatment, and prognosis. The mechanisms by which ASS1 gene dysregulation leads to metabolic abnormalities in tumor cells vary across different types of tumors. Extensive experimental studies have demonstrated that overexpression or low expression of ASS1 exhibits varying effects-either inhibitory or stimulatory proliferation-on tumor cells across different types. Restoring its expression can inhibit proliferation in some tumors lacking or downregulating ASS1 but can promote metastasis and infiltration in others (e.g., resistance to arginine deprivation therapy). Additionally, the expression level of ASS1 dynamically changes during tumorigenesis and progression. Finally, this review discusses the diagnostic, therapeutic, and prognostic value of ASS1 in future clinical practice.

Tryptophan (Trp), an essential amino acid, is solely acquired through dietary intake. It is vital for protein biosynthesis and acts as a precursor for numerous key bioactive compounds. The Kynurenine Pathway and the Indole Pathway are the main metabolic routes and are extensively involved in the occurrence and progression of diseases in the digestive, nervous, and urinary systems. In the Kynurenine Pathway, enzymes crucial to tryptophan metabolism, indoleamine-2,3-dioxygenase 1 (IDO1), IDO2, and Trp-2,3-dioxygenase (TDO), trigger tumor immune resistance within the tumor microenvironment and nearby lymph nodes by depleting Trp or by activating the Aromatic Hydrocarbon Receptor (AhR) through its metabolites. Furthermore, IDO1 can influence immune responses via non-enzymatic pathways. The Kynurenine Pathway exerts its effects on tumor growth through various mechanisms, including NAD+ regulation, angiogenesis promotion, tumor metastasis enhancement, and the inhibition of tumor ferroptosis. In the Indole Pathway, indole and its related metabolites are involved in gastrointestinal homeostasis, tumor immunity, and drug resistance. The gut microbiota related to indole metabolism plays a critical role in determining the effectiveness of tumor treatment strategies and can influence the efficacy of immunochemotherapy. It is worth noting that there are conflicting effects of the Kynurenine Pathway and the Indole Pathway on the same tumor phenotype. For example, different tryptophan metabolites affect the cell cycle differently, and indole metabolism has inconsistent protective effects on tumors in different regions. These differences may hold potential for enhancing therapeutic efficacy.

Abnormal tryptophan metabolism is closely linked with neurological disorders. Research has shown that indoleamine 2,3-dioxygenase 1 (IDO-1), the first rate-limiting enzyme in tryptophan degradation, is upregulated in Parkinson's disease (PD). However, the precise role of IDO-1 in PD pathogenesis remains elusive. In this study, we administered 1-methyl-tryptophan (1-MT), an IDO-1 inhibitor, intraperitoneally at 15 mg/kg daily for 21 days to PD mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at 30 mg/kg daily for 5 days. Our results show that IDO-1 inhibition improves behavioral performance, reduces dopaminergic neuron loss, and decreases serum quinolinic acid (QA) content and the aryl hydrocarbon receptor (AHR) expression in the striatum and colon. It also alleviates glial-associated neuroinflammation and mitigates colonic inflammation (decreasing iNOS, COX2) by suppressing the Toll-like receptor 4/nuclear factor-κB (TLR4/NF-κB) pathway. Furthermore, IDO-1 inhibition promotes hippocampal neurogenesis (increasing doublecortin positive (DCX+) cells and SOX2+ cells), which have recently been recognized as key pathological features and potential therapeutic targets in PD, likely through the activation of the BDNF/TrkB pathway. We further explored the gut-brain connection by depleting the gut microbiota in mice using antibiotics. Notably, the neuroprotective effects of IDO-1 inhibition were completely abolished in pseudo-germ-free mice (administrated an antibiotic mixture orally for 14 days prior to 1-MT treatment), highlighting the dependency of 1-MT's neuroprotective effects on the presence of gut microbiota. Finally, we found IDO-1 inhibition corrects the abnormal elevation of fecal short chain fatty acids (SCFAs). Collectively, these findings suggest that IDO-1 inhibition may represent a promising therapeutic approach for PD.

Acute kidney injury (AKI) is a major global public health concern with limited treatment options. While preclinical studies have suggested the potential of mesenchymal stem cells (MSCs) to repair and protect injured kidneys in AKI, clinical trials using transarterial MSCs transplantation have yielded disappointing results. This study aimed to investigate the feasibility and safety of minimally invasive renal subcapsular transplantation of MSCs for treating AKI in a minipig model, ultimately aiming to facilitate the clinical translation of this approach.

A novel AKI minipig model was established by combining cisplatin with hydration to evaluate the effectiveness of potential therapies. Renal subcapsular catheterization was successfully achieved under ultrasound guidance. Subsequently, the efficacy of renal subcapsular MSCs transplantation was assessed, and the biological role of the tryptophan metabolite kynurenine (Kyn) in AKI was elucidated through both in vivo and in vitro experiments.

The method of pre-hydration at 4% of body weight, followed by post-cisplatin (3.8 mg/kg) hydration at 2% of body weight, successfully established a cisplatin-induced AKI minipig model with a survival time exceeding 28 days, closely mimicking the clinical characteristics of typical AKI patients. Additionally, we discovered that multiple MSCs transplantations promoted renal function recovery more effectively than single transplantation via the renal subcapsular catheter. Furthermore, elevated levels of Kyn were observed in kidney during AKI, which activated the aryl hydrocarbon receptor (AhR)-mediated NF-κB/NLRP3/IL-1β signaling pathway in tubular epithelial cells, thereby exacerbating inflammatory injury.

Ultrasound-guided renal subcapsular transplantation of mesenchymal stem cells is a safe and effective therapeutic approach for AKI, with the potential to bring about significant clinical advancements in the future.

In recent years, there has been a growing interest in exploring the potential contribution of tryptophan (TRP) metabolism via the kynurenine (KP) and serotonin (SP) pathways in Glioblastoma (GBM) biology. This study aims to address the association between pre-operative peripheral blood levels of TRP, kynurenine (KYN), 5-hydroxy-tryptophan (5-HTP), and serotonin (5-HT) and relevant oncological outcomes in GBM IDH-wt patients.

This is a single-center, retrospective clinical study. Serum from 62 adult patients undergoing maximal safe resection of newly diagnosed glioblastoma WHO-grade 4 IDH-wt (GBM) and n = 27 healthy controls were analyzed. The variables of interest were dichotomized via maximally selected rank statistics. Kaplan Meier and Cox multivariate regression analysis were conducted to explore the single contributions of these parameters in building a predictive model of overall survival (OS) and progression-free survival (PFS) in these patients.

The mean baseline serum levels of 5-HT, KYN, and 5-HTP were significantly lower in GBM when compared to n = 27 healthy individuals (P < .001). Patients with 5-HT <78 ng/mL had a median OS of 14.4 months compared to 22.5 months in patients with increased levels (P = .01). Shorter OS was observed in patients with KYN <18 ng/mL (9.8 vs 17.5 months, P = .002), KYN/TRP <2.55 (11.4 vs 17.1, P = .002), 5-HTP/TRP <0.89 (11.5 vs 17.6 months, P = .02), and 5-HT/TRP <5.78 (13.4 vs 19.1 months, P = .002) compared to patients with high levels. Shorter PFS in patients with 5-HT <78 ng/mL (P = .04), KYN <18 ng/mL (P = .02), 5-HT/TRP <5.78 (P = .001), KYN/TRP <2.55 (P = .005). Reduced KYN, 5-HTP, and 5-HT were independent predictors of poor OS.

This study highlights an intriguing association between the degradation of TRP along the KP and SP and median survival times in GBM. Decreased KYN, 5-HTP, and 5-HT levels were associated with shorter OS.

The Epstein-Barr virus (EBV), the first identified human tumour virus, infects over 95% of the individuals globally and has the potential to induce different types of cancers. It is increasingly recognised that EBV infection not only alters cellular metabolism, contributing to neoplastic transformation, but also utilises several non-cell autonomous mechanisms to shape the metabolic milieu in the tumour microenvironment (TME) and its constituent stromal and immune cells. In this review, we explore how EBV modulates metabolism to shape the interactions between cancer cells, stromal cells, and immune cells within a hypoxic and acidic TME. We highlight how metabolites resulting from EBV infection act as paracrine factors to regulate the TME, and how targeting them can disrupt barriers to immunotherapy.

Telmisartan is an angiotensin receptor blocker (ARB) approved by the Food and Drug Administration of the US for the treatment of hypertension. It possesses unique pharmacologic properties, including the longest half-life among all ARBs; this leads to a 24-h sustained reduction of blood pressure. Besides well-known antihypertensive and cardioprotective effects, there is also strong clinical evidence that telmisartan confers renoprotection. Aryl hydrocarbon receptor (AhR) belongs to the steroid receptor family. 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) is an endogenous ligand of AhR. Cytochrome P450 (CYP) 1A1 is an AhR-target gene. In this article, we demonstrated that telmisartan (2.5-60 μM) enhanced CYP1A1 promoter activity and expressions of mRNA and protein. Telmisartan-induced CYP1A1 expression was blocked by the AhR antagonist CH-223191 in liver cell lines and was negligible in the AhR signaling-deficient mutant cells. In addition, telmisartan induced transcriptional activity mediated by aryl hydrocarbon response element in both human and mouse cells, and was able to induce AhR translocation into the nucleus. Accordingly, telmisartan is an AhR agonist. It also acted synergistically with ITE to further enhance the expression of CYP1A1 mRNA and protein. This synergistic effect was more pronounced in cells with AhR overexpression compared to those without. AhR activity has strong association with the progression of chronic renal disease. Our study demonstrated that telmisartan is an AhR agonist and has synergistic effect with ITE, an indole derivative, to potentiate the effect on AhR. This finding may provide additional clues about the mechanism of the protective effect of telmisartan on the kidney.

Parkinson's disease (PD), characterized by death of dopaminergic neurons in the substantia nigra, is the second most prevalent progressive neurodegenerative disease. However, the etiology of PD is largely elusive. This study employed the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) rodent model to examine the effectiveness of 1,4-dihydroxy-2-naphthoic acid (1,4-DHNA), an aryl hydrocarbon receptor (AhR) active gut bacteria-derived metabolite, in mitigating MPTP's motoric deficits, and the role of AhR in mediating these effects. Male C57BL/6 mice were fed daily with vehicle, 20 mg/kg 1,4-DHNA, or AhR-inactive isomer 3,7-DHNA, for 3 weeks before administration of 80 mg/kg MPTP or vehicle. Four weeks later, mice were assessed for motoric functions. Both 1,4-DHNA and 3,7-DHNA prevented MPTP-induced deficits in the motor pole test and in the adhesive strip removal test. Additionally, 1,4-DHNA improved balance beam performance and completely prevented MPTP-induced reduction in stride length. In contrast, 3,7-DHNA, an AhR-inactive compound, did not improve balance beam performance and had only a partial effect on stride length. This study suggests that natural metabolites of gut microbiota, such as 1,4-DHNA, could be beneficial to counteract the development of motor deficits observed in PD. Thus, this study further supports the hypothesis that pathological and mitigating processes in the gut could play an essential role in PD development. Moreover, this indicates that 1,4-DHNA's ability to combat various motor deficits is likely mediated via multiple underlying molecular mechanisms. Specifically, AhR is involved, at least partially, in control of gait and bradykinesia, but it likely does not mediate the effects on fine motor skills.

The evaluation of toxicity related to polychlorinated dibenzo-p-dioxins and furans (PCDD/Fs) and dioxin-like polychlorinated biphenyls (DL-PCBs) is crucial for a comprehensive risk assessment in real-world exposure scenarios. This study employed a controlled feeding experiment to investigate the metabolic effects of dioxin-like compounds (DLCs) on laying hens via feed exposure. Diets enriched with two concentrations (1.17 and 5.13 pg toxic equivalents (TEQ)/g dry weight (dw)) were administered over 14 days, followed by 28 days of clean feed. Metabolomics analyses of blood samples revealed significant metabolic variations between PCDD/Fs and DL-PCBs exposed groups and controls, reflecting the induced metabolic disruption. Distinct changes were observed in sphingosine, palmitoleic acid, linoleate, linolenic acid, taurocholic acid, indole acrylic acid, and dibutyl phthalate levels, implying possible connections between PCDD/Fs and DL-PCBs toxic effects and energy-neuronal imbalances, along with lipid accumulation and anomalous amino acid metabolism, impacting taurine metabolism. Moreover, we identified three differential endogenous metabolites-L-tryptophan, indole-3-acetaldehyde, and indole acrylic acid-as potential ligands for the aryl hydrocarbon receptor (AhR), suggesting their role in mediating PCDD/Fs and DL-PCBs toxicity. This comprehensive investigation provides novel insights into the metabolic alterations induced by PCDD/Fs and DL-PCBs in laying hens, thereby enhancing our ability to assess risks associated with their exposure in human populations.

In recent years, the role of the microbiome-gut-brain axis in the pathogenesis of Alzheimer's disease (AD) has garnered increasing attention. Specifically, tryptophan metabolism via the kynurenine pathway (KP) plays a crucial regulatory role in this axis. This study reviews how exercise regulates the microbiome-gut-brain axis by influencing kynurenine pathway metabolism, thereby exerting resistance against AD. This paper also discusses how exercise positively impacts AD via the microbiome-gut-brain axis by modulating the endocrine, autonomic nervous, and immune systems. Although the specific mechanisms are not fully understood, research indicates that exercise may optimize tryptophan metabolism by promoting the growth of beneficial microbiota and inhibiting harmful microbiota, producing substances that are beneficial to the nervous system and combating AD. The aim of this review is to provide new perspectives and potential intervention strategies for the prevention and treatment of AD by exploring the links between exercise, KP and the gut-brain axis.

The specific role of 3-hydroxyanthranilic acid(3-HAA) in oral squamous cell carcinoma (OSCC) remains unclear. This study investigated the roles of 3-HAA in OSCC and the underlying mechanism.

The effects of 3-HAA on OSCC were examined using CCK-8, colony formation, EdU incorporation assays and xenograft mouse model. The underlying mechanisms were investigated with RNA-seq, apoptosis array and cell cycle array. Short hairpin RNAs (shRNAs) were used to knockdown the expression of growth arrest and DNA damage inducible alpha (GADD45A) in OSCC cells. CCK-8 and xenograft mouse model were employed to elucidate the role of GADD45A. The binding sites between GADD45A and Yin Yang 1(YY1) were determined using luciferase reporter assay.

3-HAA was selectively down-regulated in OSCC patients and the decreasing level intensified with pathological progression. Higher expression of kynurenine 3-monooxygenase (KMO) and kynureninase (KYNU), which can increase the content of 3-HAA, was associated with poorer prognosis of OSCC patients. Exogenous 3-HAA hampered growth of OSCC cells both in vitro and in vivo. 3-HAA induced growth arrest, G2/M-phase arrest, and apoptosis of OSCC cells. RNA-seq indicated that 3-HAA significantly increased GADD45A expression. 3-HAA promoted transcription of GADD45A by transcription factor YY1. Knockdown of GADD45A significantly reversed 3-HAA-induced growth inhibition of OSCC cells in vivo and in vitro.

3-HAA induced apoptosis and cell cycle arrest of OSCC cells via GADD45A, indicating that 3-HAA and GADD45A are potential therapeutic targets for OSCC.

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor, which plays numerous and pivotal roles in human physiology and pathophysiology. Therefore, pharmacotherapeutic targeting of the AhR is a highly pertinent issue. The identification of new AhR ligands and the characterization of the interactions between the AhR ligands and AhR protein requires appropriate methodology. In spite the AhR is monomeric intracellular soluble receptor, the full-length human AhR protein has not been crystallized so far, and its isolation in a form applicable in the binding assays is highly challenging. Recent advances, including crystallization of AhR fragments, recombinant protein technologies, and cryogenic electron microscopy, allowed for exploitation of diverse experimental techniques for studying interactions between ligands and the AhR. In the current paper, we review existing AhR ligand binding assays, including their description, applicability and limitations.

Amino acid metabolism in T cells determines the therapeutic efficacy of T-cell-targeting drugs. To assess the direction of amino acid metabolism in T cells and construct related knowledge structure, we performed a bibliometric analysis aiming at amino acid metabolism in T cells utilizing studies publicized in recent 15 years. Three hundred thirty-seven related studies were downloaded from the Web of Science Core Collection (WoSCC), and the information on countries, institutes, and authors was collected and analyzed. In addition, the present research status and future trends were explored according to the results yielded from the analysis of cited references and keywords. This study revealed that publications regarding amino acid metabolism in T cells gradually increased each year. The USA is the top producer and most influential country in this field. Recent research has focused on the correlation between the metabolism of several amino acids and regulatory T cells (Tregs) and CD8+ T cells. Overall, this research offers a comprehensive exhibition on the field of amino acid metabolism in T cells, which will help researchers to study this domain more effectively and intuitively.

Immunotherapy has become a crucial strategy in cancer treatment, but its effectiveness is often constrained. Most cancer immunotherapies focus on stimulating T-cell-mediated immunity by driving the cancer-immunity cycle, which includes tumor antigen release, antigen presentation, T cell activation, infiltration, and tumor cell killing. However, metabolism reprogramming in the tumor microenvironment (TME) supports the viability of cancer cells and inhibits the function of immune cells within this cycle, presenting clinical challenges. The distinct metabolic needs of tumor cells and immune cells require precise and selective metabolic interventions to maximize therapeutic outcomes while minimizing adverse effects. Recent advances in nanotherapeutics offer a promising approach to target tumor metabolism reprogramming and enhance the cancer-immunity cycle through tailored metabolic modulation. In this review, we explore cutting-edge nanomaterial strategies for modulating tumor metabolism to improve therapeutic outcomes. We review the design principles of nanoplatforms for immunometabolic modulation, key metabolic pathways and their regulation, recent advances in targeting these pathways for the cancer-immunity cycle enhancement, and future prospects for next-generation metabolic nanomodulators in cancer immunotherapy. We expect that emerging immunometabolic modulatory nanotechnology will establish a new frontier in cancer immunotherapy in the near future.

Targeted protein degradation (TPD) modulates protein function beyond inhibition of enzyme activity or protein-protein interactions. Most degrader drugs function by directly mediating proximity between a neosubstrate and hijacked E3 ligase. Here, we identified pseudo-natural products derived from (-)-myrtanol, termed iDegs that inhibit and induce degradation of the immunomodulatory enzyme indoleamine-2,3-dioxygenase 1 (IDO1) by a distinct mechanism. iDegs boost IDO1 ubiquitination and degradation by the cullin-RING E3 ligase CRL2KLHDC3, which we identified to natively mediate ubiquitin-mediated degradation of IDO1. Therefore, iDegs increase IDO1 turnover using the native proteolytic pathway. In contrast to clinically explored IDO1 inhibitors, iDegs reduce formation of kynurenine by both inhibition and induced degradation of the enzyme and, thus, would also modulate non-enzymatic functions of IDO1. This unique mechanism of action may open up new therapeutic opportunities for the treatment of cancer beyond classical inhibition of IDO1.

Contaminant monitoring programs use wild bird eggs, but determining whether measured concentrations elicit adverse effects relies on extrapolation from toxicity studies with avian model species. Here, we directly evaluated the relationships between whole embryo contaminant concentrations and mRNA expression in liver tissue of the double-crested cormorant (Nannopterum auritum). Eggs collected from three North American sites (one from Lake Erie and two from the Salish Sea) were artificially incubated until pipping. Hepatic mRNA was analyzed with an EcoToxChip quantitative polymerase chain reaction (qPCR) array containing 354 target genes. The remaining embryo was analyzed for mercury and 95 persistent organic contaminants. Lake Erie embryos had higher concentrations of most organic contaminants than those from the Salish Sea. Sparse partial least-squares regression analysis of contaminant and gene expression data indicated that chlorinated hydrocarbons, especially polychlorinated biphenyls (PCBs), were associated with variation in gene expression. Linear correlations revealed consistent pairwise associations between chlorinated contaminants and the expression of nine genes (seven genes with PCBs and two with β-hexachlorocyclohexane). Partial least-squares discriminant analysis identified embryos from the Lake Erie site accurately. Overall, gene expression in embryos from wild-collected eggs was associated with tissue contaminant concentrations, and thus, transcriptomic measurements may serve to identify individuals or populations affected biologically by contaminants.

Polycystic ovary syndrome (PCOS) affects 6%-10% of women of reproductive age and is known to be associated with disruptions in the gut bacteria. However, the role of the gut mycobiota in PCOS pathology remains unclear. Using culture-dependent and internal transcribed spacer 2 (ITS2)-sequencing methods, we discovered an enrichment of the gut-colonizable fungus Aspergillus tubingensis in 226 individuals, with or without PCOS, from 3 different geographical areas within China. Colonization of mice with A. tubingensis led to a PCOS-like phenotype due to inhibition of Aryl hydrocarbon receptor (AhR) signaling and reduced interleukin (IL)-22 secretion in intestinal group 3 innate lymphoid cells (ILC3s). By developing a strain-diversity-based-activity metabolite screening workflow, we identified secondary metabolite AT-C1 as an endogenous AhR antagonist and a key mediator of PCOS. Our findings demonstrate that an intestinal fungus and its secondary metabolite play a critical role in PCOS pathogenesis, offering a therapeutic strategy for improving the management of the disease.

Small-molecule inhibitors of the mono (ADP) ribosyl transferase PARP7 are being evaluated asmonotherapy for tumors overexpressing PARP7 and in combination with immune checkpoint blockade. We previously showed that sensitivity to the PARP7 inhibitor (PARP7i) RBN-2397 could be enhanced by cotreatment with agonists of the aryl hydrocarbon receptor (AHRa) in cell lines that show strong intrinsic sensitivity to RBN-2397. In this study, we demonstrated that a range of tumor cell lines that are relatively insensitive to PARP7i or AHRa as individual agents are unexpectedly profoundly sensitive to their combination. Our data show that this synergistic response is dependent on the AHR/AHR nuclear translocator and is associated with increased levels of nuclear AHR and increased transcription of AHR target genes. In some hormone receptor-positive cell lines, we find that combination treatment is associated with proteasomal turnover of the steroid hormone receptors, androgen receptor and estrogen receptor. Both wild-type and hormone-resistant mutant forms of these receptors are degraded upon treatment with AHRa and PARP7i in breast and prostate cancer models. These results suggest that combining PARP7i with AHRa may extend the utility of these drugs to a wider range of tumors, including those that are refractory to hormone therapy.

As a result of a long evolutionary history, serotonin plays a variety of physiological roles, including neurological, cardiovascular, gastrointestinal, and endocrine functions. While many of these activities can be accommodated within the serotoninergic activity, recent findings have revealed an unsuspected role of serotonin in orchestrating host and microbial dialogue at the tryptophan dining table, to the benefit of local and systemic homeostasis. Herein we review the dual role of serotonin at the host-microbe interface and discuss how unraveling the interconnections among the host and microbial pathways of tryptophan degradation may help to accommodate the versatility of serotonin in physiology and pathology.

Although tryptophan (Trp) is the largest and most structurally complex amino acid, it is the least abundant in the proteome. Its distinct indole ring and high carbon content enable it to generate various biologically active metabolites such as serotonin, kynurenine (Kyn), and indole-3-pyruvate (I3P). Dysregulation of Trp metabolism has been implicated in diseases ranging from depression to cancer. Investigating Trp and its metabolites in healthy tissues offers pathways to target disease-associated disruptions selectively, while preserving essential functions. In this study, we comprehensively mapped Trp metabolites across the Kyn, serotonin, and I3P pathways, as well as the microbiome-derived metabolite tryptamine, in C57BL/6 mice. Our comprehensive analysis covered 12 peripheral organs, the central nervous system, and serum in both male and female mice at three life stages: young (3 weeks), adult (54 weeks), and aged (74 weeks). We found significant tissue-, sex-, and age-specific variations in Trp metabolism, with notably higher levels of the oncometabolites I3P and Kyn in aging males. These findings emphasize the value of organ-specific analysis of Trp metabolism for understanding its role in disease progression and identifying targeted therapeutic opportunities.

Precision oncology's implementation in clinical practice faces significant constraints due to the inadequacies in tools for detailed patient stratification and personalized treatment methodologies. Dysregulated tryptophan metabolism has emerged as a crucial factor in tumor progression, encompassing immune suppression, proliferation, metastasis, and metabolic reprogramming. However, its precise role in clear cell renal cell carcinoma (ccRCC) remains unclear, and predictive models or signatures based on tryptophan metabolism are conspicuously lacking.

The influence of tryptophan metabolism on tumor cells was explored using single-cell RNA sequencing data. Genes involved in tryptophan metabolism were identified across both single-cell and bulk-cell dimensions through weighted gene co-expression network analysis (WGCNA) and its single-cell data variant (hdWGCNA). Subsequently, a tryptophan metabolism-related signature was developed using an integrated machine-learning approach. This signature was then examined in multi-omics data to assess its associations with patient clinical features, prognosis, cancer malignancy-related pathways, immune microenvironment, genomic characteristics, and responses to immunotherapy and targeted therapy. Finally, the genes within the signature were validated through experiments including qRT-PCR, Western blot, CCK8 assay, and transwell assay.

Dysregulated tryptophan metabolism was identified as a potential driver of the malignant transformation of normal epithelial cells. The tryptophan metabolism-related signature (TMRS) demonstrated robust predictive capability for overall survival (OS) and progression-free survival (PFS) across multiple datasets. Moreover, a high TMRS risk score correlated with increased tumor malignancy, significant metabolic reprogramming, an inflamed yet dysfunctional immune microenvironment, heightened genomic instability, resistance to immunotherapy, and increased sensitivity to certain targeted therapeutics. Experimental validation revealed differential expression of genes within the signature between RCC and adjacent normal tissues, with reduced expression of DDAH1 linked to enhanced proliferation and metastasis of tumor cells.

This study investigated the potential impact of dysregulated tryptophan metabolism on clear cell renal cell carcinoma, leading to the development of a tryptophan metabolism-related signature that may provide insights into patient prognosis, tumor biological status, and personalized treatment strategies. This signature serves as a valuable reference for further exploring the role of tryptophan metabolism in renal cell carcinoma and for the development of clinical applications based on this metabolic pathway.

Regulatory T cell (Tregs) predominantly maintain the immune balance and prevent autoimmunity via their immunosuppressive functions. However, tumor-infiltrating Tregs (TI-Tregs) may mediate tumor immune tolerance in complex tumor microenvironments, resulting in poor prognosis. Distinguishing specific TI-Treg subpopulations from peripheral Tregs and intratumoral conventional T cells (Tconvs) has recently emerged as an important topic in antitumor therapy. In this review, we summarize novel therapeutic approaches targeting both the metabolic pathways and hallmarks of TI-Tregs in preclinical and clinical studies. Although the phenotypic and functional diversity of TI-Tregs remains unclear, our review provides new insights into TI-Treg-based therapies and facilitates precision medicine for tumor treatment.

Tryptophan (Trp) metabolism is linked to health and disease, with indoleamine 2,3-dioxygenase 1 (IDO) being a key enzyme in its breakdown outside the liver. This process produces metabolites that influence metabolic and inflammatory responses. A distinctive feature of the gut is its involvement in three major Trp catabolic pathways: the IDO-driven kynurenine pathway, bacteria-produced indoles, and serotonin. Dysregulation of these pathways is associated with gastrointestinal and chronic inflammatory diseases. Understanding these mechanisms could reveal how gut function affects overall systemic health and disease susceptibility. Here, we review current insights into Trp metabolism, its impact on host physiology and cardiometabolic diseases, and its role in the gut-periphery connection, highlighting its relevance for therapeutic innovation.