Search Results (6,686)

High-intensity intermittent exercise can acutely alter circulating cytokines, but findings are heterogeneous. The aim was to systematically synthesize acute blood cytokine responses after a single high-intensity intermittent exercise session in humans. PubMed, Scopus, and Web of Science Core Collection, plus reference screening. Eligibility criteria included original human studies measuring serum or plasma cytokines pre-exercise and at least one post-exercise time point after high-intensity intermittent exercise. Sampling was mapped to prespecified recovery windows. Risk of bias was assessed using RoB 2 (randomized trials) and the Joanna Briggs Institute quasi-experimental tool. Narrative synthesis was used. From 2077 records, 45 studies were included. Most protocols used cycling or treadmill modalities, and sampling clustered in the immediate and early recovery windows. Interleukin 6 most consistently increased after exercise, whereas tumor necrosis factor alpha, interleukin 10, and other mediators showed mixed or context-dependent changes. Risk of bias was commonly rated as some concerns, with frequent limitations in pre-analytical control and reporting. Across included studies, high-intensity intermittent exercise tended to elicit a short-lived myokine-dominant inflammatory signal, characterized primarily by an increase in circulating interleukin 6, most often detected in the immediate and early recovery windows. Conflicting findings for tumor necrosis factor alpha, interleukin 10, redox-related outcomes, and less frequently measured mediators were best explained by a small set of dominant moderators: post-exercise sampling window, exercise dose/internal load, participant metabolic and training phenotype, and pre-analytical or assay-related heterogeneity. Registration: Open Science Framework (osf.io/wspr6; 17 February 2026). Full article

Background and Clinical Significance: Sarcomatoid renal cell carcinoma is a rare and highly aggressive variant of renal cell carcinoma, frequently associated with advanced-stage disease, early metastatic spread, and poor prognosis. Although immune checkpoint inhibitors have improved outcomes in metastatic renal cell carcinoma, particularly in tumors with sarcomatoid differentiation, they may also induce severe immune-related adverse events involving multiple organ systems. Case Presentation: We report the case of a 54-year-old woman with metastatic clear cell renal cell carcinoma with sarcomatoid differentiation, previously treated with nivolumab plus ipilimumab and subsequently with pazopanib, who was admitted with severe dehydration, repeated vomiting, marked asthenia, lower-limb-predominant muscle weakness, and inability to maintain orthostatism. Laboratory investigations revealed severe hyperkalemia, hyponatremia, hypoglycemia, anemia, thrombocytopenia, and prerenal acute kidney injury. The patient had a previous history of severe endocrine immune-related toxicity, including autoimmune hypophysitis and hypothyroidism, which had led to discontinuation of immunotherapy. Following fluid resuscitation, electrolyte correction, and supportive treatment, the metabolic abnormalities resolved and renal function improved significantly. Given the severity of the muscle weakness, a possible immune-mediated neuromuscular adverse event was also considered, although hyperkalemia remained a plausible contributing factor. Conclusions: This case highlights the complex interplay between prior immune checkpoint inhibitor exposure, endocrine dysfunction, metabolic decompensation, and possible neuromuscular involvement in metastatic sarcomatoid renal cell carcinoma. Early recognition, careful differential diagnosis, and multidisciplinary management are essential to prevent rapid clinical deterioration and optimize outcomes in patients with complex immune-related toxicities. Full article

The tumor microenvironment (TME) acts as a major barrier to effective drug delivery and contributes to drug resistance in solid tumors. Hypoxia, acidosis, and elevated interstitial fluid pressure limit drug penetration, while cancer-associated fibroblasts and immunosuppressive cells promote survival signaling, drug efflux, and metabolic adaptation. Polymeric drug delivery systems offer a promising strategy to address these barriers because their structures can be precisely engineered and designed to respond to TME-specific stimuli. These properties enable controlled drug release at tumor sites and help improve therapeutic efficacy while reducing systemic limitations. This review discusses how physicochemical and cellular components of the TME contribute to drug resistance and how polymeric nanomedicines can be designed to overcome these barriers. In addition, it examines key challenges that limit clinical translation, including tumor heterogeneity, variable enhanced permeability and retention effects, manufacturing scalability, and regulatory requirements. Finally, this review highlights the future direction of polymer nanomedicine and focuses specifically on developing rational material design, enhancing preclinical models, and developing clinically appropriate strategies to combat TME-mediated drug resistance. Full article

Colorectal cancer (CRC) progression stems from dynamic metabolic crosstalk between malignant cells and the tumor microenvironment (TME). Among stromal components, cancer-associated fibroblasts (CAFs) have emerged as pivotal metabolic drivers rather than mere structural elements. Specifically, evidence indicates that mitochondrial reprogramming in CAFs significantly orchestrates tumor growth, therapeutic resistance, and immune evasion in CRC. This review synthesizes recent insights into how CAF mitochondrial dynamics and metabolic reprogramming dictate CRC biology. We first examine the functional diversity of CAF subpopulations and their distinct mitochondrial requirements. We then contrast mitochondrial dynamics—including fission–fusion balance and mitophagy—between CRC cells and CAFs, highlighting how tumor-derived signals modulate stromal mitochondrial function. We systematically evaluate key regulatory pathways of CAF mitochondrial reprogramming, including TGF-β/HIF-1α, ROS-NF-κB, PI3K–AKT–mTOR, AMPK–PGC-1α, YAP/TAZ mechanotransduction, and mtDNA-mediated cGAS–STING signaling. Furthermore, we discuss how remodeled CAF mitochondria foster metabolic symbiosis via lactate, ketone, and glutamine shuttling; maintain redox homeostasis through the NADPH–glutathione axis and UCP2; and establish immunosuppressive niches via mitochondrial stress signaling. Collectively, these mechanisms drive resistance to chemotherapy, targeted agents, radiotherapy, and immunotherapy. By integrating mitochondrial metabolism, stromal signaling, and clinical responses, this review identifies CAF mitochondria as an actionable target within the CRC TME. Targeting these CAF-specific pathways offers a novel strategy to disrupt tumor–stroma metabolic cooperation and overcome treatment resistance in colorectal cancer. Full article

Clear cell renal cell carcinoma (ccRCC) is increasingly recognized as a lipid-addicted malignancy in which de novo lipogenesis (DNL) supports tumor growth, survival, and treatment resistance. ccRCC-specific genetic alterations, particularly loss of VHL and activation of hypoxia-inducible factor (HIF) signaling, promote SREBP-mediated upregulation of key lipogenic enzymes, including ATP-citrate lyase (ACLY), acetyl-CoA carboxylase (ACC), fatty acid synthase (FASN), and stearoyl-CoA desaturase 1 (SCD1). These pathways support membrane biogenesis and redox balance while also promoting metabolic flexibility, enabling adaptation to therapeutic and microenvironmental stresses. Emerging preclinical studies suggest that pharmacological inhibition of lipogenic enzymes, either alone or in combination with tyrosine kinase inhibitors, mTOR inhibitors, HIF-2α antagonists, or immune checkpoint blockade, may suppress ccRCC progression. However, most therapeutic data remain limited to preclinical models, and clinical validation is still lacking. This review synthesizes recent advances in molecular regulation and therapeutic targeting of DNL in ccRCC and discusses the challenges and future opportunities to improve mechanistic understanding and explore potential therapeutic applications. Full article

Cancer stem cells (CSCs) are a highly influential population of tumor cells involved in tumor initiation, progression, metastasis, recurrence, and resistance to therapy. Although CSCs have been widely investigated, their behavior cannot be understood solely through intrinsic cellular features, as these cells strongly depend on a specialized supportive microenvironment known as the CSC niche. In this review, we discuss the CSC niche as a dynamic and therapeutically relevant ecosystem that is distinct from, but closely connected with, the broader tumor microenvironment. Particular attention is given to stromal cells, immune cells, endothelial cells, extracellular matrix components, hypoxia, cytokines, chemokines, and metabolic stress as regulators of CSC self-renewal, plasticity, dormancy, immune escape, epithelial–mesenchymal transition, metastatic dissemination, and survival under therapeutic pressure. We further consider how CSC–niche interactions contribute to pre-metastatic niche formation and tumor relapse. Finally, we outline emerging therapeutic strategies aimed at disrupting CSC-supportive signals, including approaches targeting developmental pathways, angiogenesis, hypoxia, extracellular matrix remodeling, immunosuppressive networks, and cytokine-mediated communication. Overall, this review emphasizes that targeting the CSC-supportive microenvironment is essential for limiting metastasis, recurrence, and long-term treatment failure. Full article

Breast cancer remains the most frequently diagnosed malignancy among women worldwide, while metabolic dysfunction-associated steatotic liver disease (MASLD) represents the leading cause of chronic liver disease, reflecting a global burden of metabolic dysfunction. Increasing evidence suggests that MASLD is associated with breast cancer development and progression; however, whether this relationship reflects an independent effect of hepatic metabolic dysfunction or the broader metabolic environment remains uncertain. This review synthesizes current epidemiological, clinical, and mechanistic data linking hepatic metabolic dysfunction to breast carcinogenesis. Population-based studies consistently demonstrate an association between hepatic steatosis and increased breast cancer incidence, particularly in postmenopausal and metabolically vulnerable populations, as well as poorer oncological outcomes. Mechanistically, MASLD promotes a systemic pro-tumorigenic environment through interconnected pathways, including insulin resistance, hormonal dysregulation with increased estrogen bioavailability, chronic inflammation, oxidative stress, lipid metabolic reprogramming, and gut–liver axis disruption. Hepatokines, particularly fibroblast growth factor 21 (FGF21), emerge as key mediators of tumor progression and potential biomarkers of metabolic vulnerability, while Fetuin-A and angiopoietin-like protein 8 (ANGPTL8) further support the liver’s endocrine role in oncogenic signaling. Preclinical evidence highlights fatty acid oxidation as a metabolic dependency in aggressive breast cancer subtypes, suggesting novel therapeutic targets. Despite consistent associations, causality remains unproven. Future prospective studies are needed to determine whether targeting metabolic dysfunction can improve breast cancer prevention and outcomes. Full article

Background: A20, encoded by tumor necrosis factor alpha-induced protein 3 (TNFAIP3), is a key negative regulator of NF-κB signaling with context-dependent functions in cancer. Its role in renal cell carcinoma (RCC), particularly clear-cell RCC (ccRCC), remains incompletely defined. Methods: Public GEO transcriptomic data from 23 controls and 32 ccRCC samples were analyzed using gene set enrichment analysis (GSEA). A20-overexpressing HEK293 and 786-O cells were assessed by functional assays and transcriptomic profiling. Eight ccRCC FFPE samples were profiled to compare A20-associated transcriptional patterns with cell-line data. Targeted DNA sequencing was performed in 11 ccRCC and 8 papillary RCC samples, and whole-exome sequencing was conducted in A20-overexpressing 786-O cells. Key genes were further evaluated using Kaplan-Meier survival analysis in 530 ccRCC patients and TCGA-KIRC data comprising 533 primary tumors and 72 normal samples. Results: GEO analysis showed significant TNFAIP3/A20 upregulation in ccRCC (p = 3.96 × 10⁻⁵) and enrichment of NF-κB-related gene sets (p = 0.01). A20 overexpression produced distinct phenotypes in HEK293 and 786-O cells. In HEK293 cells, A20 increased BIK and ARHGAP6 expression and was associated with increased apoptosis and reduced wound closure. In 786-O cells, A20 suppressed ARHGAP6 and APAF1 and was associated with increased proliferation, enhanced wound closure, and reduced apoptosis relative to EV controls. A20-high ccRCC samples showed enrichment of NF-κB, TGF-β, DNA repair, mTOR/metabolic, hypoxia, and proteasome-related pathways. Genomic analyses identified alterations in NF-κB-related genes, including CARD10 and IRAK1. Conclusions: A20/TNFAIP3 may exert cell-context-dependent effects in RCC and is associated with tumor-relevant transcriptional and genomic alterations requiring further validation. Full article

Background: Pancreatic ductal adenocarcinoma (PDAC) is associated not only with tumor progression but also with profound metabolic and nutritional disturbances. Thyroid hormone homeostasis may reflect this systemic response; however, perioperative data in PDAC remain limited. We aimed to assess perioperative changes in thyroid-related parameters in patients with PDAC undergoing different types of surgical management and to explore their associations with nutritional, metabolic, and tumor-burden variables. Methods: We performed a retrospective single-center study including 101 patients with PDAC. Thyroid-related and metabolic laboratory parameters were assessed before surgery and again 4–6 weeks later. The analyzed variables included thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), the FT3/FT4 ratio, albumin, total protein, glucose, insulin, HbA1c, lipid parameters, and CA 19-9. Patients were analyzed according to resectional versus non-resectional treatment and according to four procedure types. The primary endpoint was perioperative change in the FT3/FT4 ratio. Results: At baseline, resectional patients had significantly higher FT3 and FT3/FT4 ratio values and lower FT4 and CA 19-9 levels than non-resectional patients. In the whole cohort, FT3 and the FT3/FT4 ratio decreased significantly after treatment, whereas TSH increased, and FT4 remained unchanged. These endocrine changes occurred in parallel with significant declines in albumin, total protein, glucose, insulin, HbA1c, and HDL cholesterol, together with an increase in triglyceride levels. Baseline FT3 and FT3/FT4 ratios correlated positively with albumin and total protein and negatively with CA 19-9. Although perioperative changes did not differ significantly between resectional and non-resectional groups except for triglycerides, significant procedure-dependent differences were observed across the four surgical categories for FT3, FT4, TSH, and the FT3/FT4 ratio; glucose; insulin; and triglycerides. The prevalence of low-T3 syndrome increased from 11.1% preoperatively to 38.7% postoperatively. Conclusions: In PDAC, perioperative changes in thyroid hormone indices are pronounced and strongly depend on the type of surgical management. FT3 and the FT3/FT4 ratio appear to reflect systemic metabolic and nutritional adaptation as well as disease burden rather than acting as tumor-specific markers. Full article

Locally advanced rectal cancer is commonly treated using total neoadjuvant therapy (TNT), which integrates radiotherapy with systemic chemotherapy to improve tumor downstaging, local control, and long-term oncologic outcomes. Despite its central role in treatment, responses to radiotherapy remain highly heterogeneous. While some tumors undergo complete regression, others exhibit intrinsic or acquired treatment resistance, resulting in incomplete tumor control while experiencing treatment-related toxicity. Understanding the biological determinants that govern radiation sensitivity in rectal cancer, therefore, represents a major clinical challenge. Ionizing radiation induces tumor cell death primarily through the generation of reactive oxygen species (ROS) and DNA damage, particularly DNA double-strand breaks. In addition to nuclear DNA injury, radiation-induced oxidative stress can initiate lipid peroxidation within cellular membranes. When lipid peroxide accumulation exceeds the capacity of cellular antioxidant systems, this process can trigger ferroptosis, an iron-dependent form of regulated cell death driven by phospholipid oxidation. Ferroptotic susceptibility is regulated by interconnected metabolic pathways, including cystine transport through system Xc⁻ (SLC7A11/SLC3A2), glutathione synthesis, glutathione peroxidase-4 (GPX4) activity, iron metabolism, and membrane lipid remodeling. Recent evidence further indicates that ferroptosis intersects with antitumor immunity. Ferroptotic tumor cells release oxidized lipid mediators and damage-associated molecular signals that can influence immune activation, while interferon-γ produced by activated CD8⁺ T cells during immune checkpoint blockade suppresses SLC7A11 expression, limiting cystine uptake and promoting ferroptotic tumor cell death. These findings suggest that ferroptosis represents a mechanistic interface between tumor metabolic vulnerability and immune-mediated cytotoxicity. This interaction is particularly relevant in colorectal cancer biology, where immune checkpoint inhibitors demonstrate clinical benefit primarily in tumors with deficient mismatch repair or microsatellite instability-high (MSI-H) status. The vast majority of rectal cancers are microsatellite stable (MSS) and exhibit limited responsiveness to immunotherapy due to reduced immunogenicity and immune exclusion within the tumor microenvironment. Strategies capable of increasing tumor immunogenicity in this setting are therefore of considerable interest. In this review, we examine the molecular mechanisms linking radiation-induced oxidative stress to ferroptosis and tumor immunity in colorectal cancer, while focusing on the clinical context of radiotherapy in rectal cancer. We discuss how lipid metabolism, iron homeostasis, cysteine-dependent antioxidant systems, and immune signaling pathways converge to regulate ferroptotic vulnerability and radiation response. We further explore the therapeutic potential of integrating radiotherapy, ferroptosis-targeting strategies, and immunotherapy to overcome radioresistance and improve treatment outcomes in colorectal cancer. Full article

Background: CAD (Carbamoyl-Phosphate Synthetase 2, Aspartate Transcarbamylase, and Dihydroorotase) is a pivotal tri-functional enzyme complex associated with the rate-limiting steps of the de novo pyrimidine biosynthetic pathway. Despite its established metabolic role, the multi-dimensional involvement of CAD in the pan-cancer landscape—specifically regarding its regulation of the metabolic–immune axis and its impact on immunotherapy response—remains to be fully elucidated. Methods: We performed a systematic pan-cancer multi-omics analysis integrating TCGA, GTEx, and DepMap datasets to evaluate CAD expression, genomic alterations, and diagnostic potential. In addition, multiple immunotherapy cohorts were integrated for meta-analysis, and metabolomic data were incorporated to explore CAD-associated metabolic features. Results: CAD was significantly upregulated in 17 cancer types, with protein-level evidence supporting this trend. CAD also showed high diagnostic accuracy in several malignancies, particularly LAML and CHOL (AUC approximately 1.0). In immunotherapy-related analyses, CAD expression was positively associated with TMB, MSI, and initial therapeutic response, but was also linked to worse long-term overall survival in pooled cohorts (HR = 1.42, 95% CI: 1.19–1.70). Integrative metabolomic analyses further suggested that high CAD expression was associated with pyrimidine metabolite accumulation and altered amino acid metabolism, indicating a potential link between CAD-related metabolic reprogramming and the tumor immune microenvironment. Conclusions: CAD may represent a promising candidate biomarker across multiple malignancies. Notably, its association with immunotherapy-related features, together with the observed discordance between response-associated signals and long-term survival, warrants further mechanistic and clinical validation. Full article

Gastric cancer (GC) is the fifth leading cause of cancer-related mortality worldwide. Treatment options for advanced GC remain limited, owing to the frequent emergence of drug resistance. This highlights an urgent clinical need for novel therapeutic targets. Abnormal energy metabolism is a hallmark feature of cancer. MYC_V1-driven metabolic reprogramming plays a pivotal role in tumor progression. However, the specific mechanisms by which MYC_V1-related genes regulate energy metabolism in GC remains poorly understood. We employed single-sample gene set enrichment analysis (ssGSEA) to evaluate multiple tumor hallmarks in GC. A prognostic risk model was constructed based on MYC_V1-related genes, with the risk score (RS) used to stratify patients into distinct risk groups. A nomogram was developed and validated using calibration curves. Through the systematic molecular docking screening of 8327 compounds, potential therapeutic agents were identified. Functional experiments, including the CCK-8 assay, wound-healing assay and ATP production assay, were conducted to validate the role of NDUFV2 in GC progression. This study identified MYC_V1 as the primary risk factor affecting the overall survival (OS) in GC patients (p = 0.038). A prognostic risk model was successfully constructed based on eight MYC_V1-related genes (KPNA2, MCM2, MCM4, NDUFV2, PDK4, MPO, IGFBP1, and STC2). The RS was confirmed as an independent prognostic factor. The prognostic risk model accurately predicted patient 1-, 3-, and 5-year OS in GC patients. Tumor microenvironment analysis revealed significant differences in immune cell infiltration patterns between high-risk and low-risk groups. High-throughput drug screening and molecular docking identified camptothecin (CPT) and vinblastine as showing strong therapeutic potential for high-risk patients. Experimental validation demonstrated that NDUFV2 was significantly overexpressed in GC tissues, and its knockdown markedly suppressed the proliferation, migration capacity, and intracellular ATP production in GC cells, confirming the critical role of NDUFV2 in GC progression. These findings establish NDUFV2 as a potential therapeutic target in GC. Full article

Squalene is a triterpene with potent biological activities. Squalene (C₃₀H₅₀) is a linear polyunsaturated hydrocarbon composed of six isoprene units and six carbon–carbon double bonds. It serves as an essential precursor for sterols, steroid hormones, and vitamin D in humans and exhibits antioxidant, anti-tumor, and lipid-regulating properties. In plants, squalene is produced via the mevalonate (MVA) and 2-C-methyl-D-erythritol-4-phosphate (MEP) pathways. The key rate-limiting enzymes in these pathways include 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), farnesyl diphosphate synthase (FPS), and squalene synthase (SQS). Camellia oleifera, a unique woody oil crop native to China, is valued for its high-quality edible oil and as a rich natural source of squalene. This review provides a systematic overview of recent progress in squalene biosynthesis in C. oleifera. It summarizes the structural characteristics and biosynthetic routes. It further elaborates on the multi-level regulatory network modulated by transcription factors (WRKY, bHLH, MYB, and ERF), phytohormones (jasmonic acid, abscisic acid, and gibberellin), and abiotic factors (light and drought). Notably, this review distinguishes earlier foundational studies from recent breakthroughs and integrates emerging progress on squalene’s non-canonical functions and pathway crosstalk. It further highlights novel regulatory mechanisms unique to C. oleifera (e.g., CoWRKY15, CoMYB1, and CoMYC2). By bridging molecular regulation with practical breeding and metabolic engineering, this review lays a solid theoretical foundation for cultivating high-squalene C. oleifera varieties. It represents a prominent innovation relative to previously published studies. Full article

L-asparaginase (ASNase) is a paradigmatic amino-acid depletion therapy that induces systemic asparagine starvation and remains foundational in acute lymphoblastic leukemia (ALL). Amino-acid metabolism constitutes a fundamental therapeutic vulnerability in hematologic malignancies, yet the determinants of response to systemic asparagine depletion remain incompletely defined. Asparagine synthetase (ASNS) regulates intracellular asparagine biosynthesis and functions as a stress-responsive metabolic node embedded within adaptive nutrient-sensing pathways. Emerging transcriptomic and proteomic evidence demonstrates that reduced ASNS expression is enriched in biologically distinct subsets of acute myeloid leukemia (AML), particularly those characterized by immature differentiation states and cytogenetic features associated with metabolic fragility, including inv(16) and chromosome 7--associated disease. Clinical experience in natural killer/T-cell (NK/T-cell) neoplasms provides proof-of-principle that enzymatic asparagine depletion can achieve durable therapeutic efficacy in tumors intrinsically dependent on extracellular amino-acid supply, establishing extranodal NK/T-cell lymphoma (ENKTL) as a mechanistically aligned anchor indication beyond acute lymphoblastic leukemia. Integrative molecular analyses further indicate that ASNS deficiency functions as a permissive rather than deterministic biomarker, with therapeutic response modulated by lineage-specific metabolic wiring, adaptive stress signaling, and microenvironmental nutrient buffering. Advances in protein-anchored diagnostic platforms, including intracellular flow cytometry and quantitative proteomics, now enable operationalization of ASNS as a clinically actionable stratification marker. Mechanistic studies also suggest that amino-acid depletion may interact with apoptotic signaling networks, supporting rational combination strategies with targeted agents such as BCL-2 inhibitors. Collectively, these findings support a conceptual framework in which ASNS-low defines a context-dependent metabolic vulnerability rather than a uniform disease-wide predictor, underscoring the need for prospective biomarker-enriched clinical trials to establish ASNS-guided amino-acid depletion as a precision oncology strategy across heterogeneous myeloid and lymphoid malignancies. Full article

Background: Colorectal cancer (CRC) progression is associated with tumor metabolic reprogramming and an immunosuppressive tumor microenvironment, yet coordinated metabolic interactions between malignant epithelial and immune cells remain unclear. This study aimed to characterize metabolic crosstalk in CRC, validate spatial organization, and develop a metabolism-based prognostic model. Methods: Six CRC single-cell RNA sequencing datasets were integrated to identify cell populations, evaluate metabolic pathway activity, and infer cell–cell communication. Spatial transcriptomics was used to assess regional co-enrichment of key cell-subset signatures and metabolic activities. Bulk transcriptomic cohorts and targeted metabolomics data were analyzed for pathway-level support. Patients were stratified using metabolic features of selected subsets, followed by protein–protein interaction analysis and elastic net modeling. Results: Across six scRNA-seq datasets comprising 431,217 cells from 173 samples (107 tumor, 60 normal, and 6 border), we identified a metabolically reprogrammed malignant epithelial subset (SLC6A20+ epithelial cells) and an immunosuppressive SPP1+ tumor-associated macrophage (TAM) subset. Both exhibited elevated glycolysis, vitamin B6 metabolism, and aromatic amino acid metabolism. Spatial transcriptomics supported regional co-enrichment of their signatures and shared metabolic activities within the same tumor regions. Independent bulk transcriptomic cohorts and targeted metabolomics further supported these pathway alterations. Cell–cell communication analysis revealed extensive bidirectional ligand-receptor interactions. Based on metabolic features of these subsets, patients were stratified into two prognostic groups. A 14-gene elastic net signature predicted the high-risk subtype with consistent performance across independent cohorts. Conclusions: SLC6A20+ epithelial cells and SPP1+ TAMs showed coordinated, transcriptome-inferred metabolic programs and predicted bidirectional communication in CRC. These features provide candidate biologically interpretable biomarkers and a metabolism-based prognostic model for patient stratification. Full article