Neuroblastoma (NB) is the most common extracranial solid tumour of childhood and remains a leading cause of paediatric cancer mortality, particularly in high-risk disease driven by MYCN amplification. Although MYCN is a central oncogenic driver, its role as a transcription factor has limited direct therapeutic targeting, shifting attention toward downstream metabolic and microenvironmental dependencies. Increasing evidence indicates that MYCN-driven metabolic rewiring extends beyond tumour-intrinsic processes to reshape the tumour microenvironment (TME), influencing immune composition and stromal dynamics. Recent advances in single-cell and spatial profiling technologies have revealed substantial heterogeneity within the NB TME, highlighting complex interactions between tumour cells, immune populations, and stromal components. Among these, cancer-associated fibroblasts (CAFs) have emerged as key regulators of extracellular matrix architecture, immune modulation, and metabolic crosstalk. However, CAF identity, functional diversity, and lineage relationships in NB remain incompletely defined, with significant overlap between tumour-intrinsic mesenchymal programs and stromal fibroblast signatures. In this review, we synthesise current understanding of MYCN-driven metabolic reprogramming and its impact on CAF heterogeneity and immune regulation. We integrate insights from adult cancers with emerging data in NB to critically evaluate CAF functional states, including inflammatory and myofibroblastic programs, and their roles in shaping tumour progression, immune exclusion, and therapeutic response. By framing NB as a MYCN-remodelled tumour ecosystem, this review identifies key knowledge gaps in stromal biology and highlights the need to resolve CAF heterogeneity and tumour–stroma interactions. These insights have broader implications for MYC-driven malignancies and support the development of integrated therapeutic strategies targeting both tumour cells and their supportive microenvironment.
Neuroblastoma (NB) is a highly heterogeneous pediatric cancer in which chemotherapy resistance and poor prognosis are tightly linked to the tumor microenvironment (TME). Yet, how chemotherapy reshapes stromal components, particularly cancer-associated fibroblasts (CAFs), and the clinical implications of these alterations remain unclear. Here, by integrating single-cell, spatial, and bulk RNA-seq data from nine NB datasets, we systematically characterized chemotherapy-induced TME remodeling. Fibroblast subtypes were defined through clustering, stemness estimation, and functional enrichment analyses, revealing SFRP2
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inflammatory CAFs (iCAFs) as the dominant fibroblast population enriched after chemotherapy in adrenal NB TME. These SFRP2
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iCAFs exhibited high expression of SFRP2, FBLN1, and chemokines CXCL2 and CXCL3, and were found to promote angiogenesis by signaling to endothelial cells through the CCL2/CXCL2/3/8–ACKR1 axis. Building on the chemotherapy-associated gene expression changes in adrenal NB tumor cells, we developed a 6-gene prognostic model, termed NBTRP. The NBTRP robustly stratified patient survival across multiple cohorts and was associated with reduced cytotoxic T cell infiltration, increased tumor purity, and distinct drug sensitivity profiles. High NBTRP scores predicted enhanced sensitivity to chemotherapeutic agents such as vinblastine and etoposide, as well as improved response to anti–PD-L1 immunotherapy. Functional validation further identified SERPINF1, the top NBTRP feature, as a key effector that promoted NB cell invasion in vitro and modulated drug responses to vincristine, etoposide, cisplatin and cyclophosphamide. Together, our findings uncover SFRP2
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iCAFs as pivotal mediators of post-chemotherapy TME remodeling and establish NBTRP and SERPINF1 as clinically relevant biomarkers that bridge tumor–stroma dynamics with prognosis and therapeutic guidance in adrenal neuroblastoma.
Jun Wu, Jian Gu, Guodong Li et al.· Cell Death & Disease· 0 citations
Gastric cancer (GC) remains a major global health challenge characterized by poor prognosis and high mortality rates, despite advances in anticancer therapies. Increasing evidence indicates that GC is a highly stromal-rich tumor, with cancer-associated fibroblasts (CAFs) serving as key stromal components of the tumor microenvironment (TME). CAFs exhibit substantial metabolic heterogeneity, such that distinct CAF subtypes demonstrate intrinsic differences and dynamic remodeling in glucose, lipid and amino acid metabolism. This metabolic reprogramming represents not only functional diversity but also an adaptive response to microenvironmental stressors, including tumor-derived signals, hypoxia, nutrient fluctuations and oxidative stress. Through these adaptations, CAFs engage in extensive crosstalk with tumor and immune cells, thereby contributing to microenvironmental remodeling. Due to their critical role and abundance in GC, CAFs have emerged as promising therapeutic targets. The present review summarizes the origins, characteristics and heterogeneity of CAFs in GC and discusses their interactions with the TME. In addition, it summarizes the metabolic heterogeneity of CAFs, explores potential metabolism-targeted therapeutic strategies and outlines the broader impact of CAFs on the TME.
Qilu Fang, Neng Lv, Shuwei Yu et al.· Oncology Letters· 0 citations
Progress in the understanding of ATC biology is highlighted, with a focus on driver genetic alterations, metabolic plasticity and microenvironmental interactions that underpin its exceptional aggressiveness, to provide a rationale for the design of multimodal therapeutic strategies urgently needed to improve outcomes for patients with ATC.
The tumour microenvironment (TME) consists of a complex ecosystem of tumour cells, stromal elements, extracellular matrix, fibroblasts and diverse immune-cell populations. Although traditional cancer therapies have primarily focused on eliminating tumour cells, subsequent advances highlighted the importance of modulating immune cells within the TME to enhance anti-tumour immunity. More recently, a major conceptual shift has emerged: targeting nutrient metabolism as a therapeutic strategy. Because tumours create a hypoglycaemic, metabolically restrictive niche, both cancer cells and infiltrating immune cells increasingly rely on lipid uptake, storage and catabolism to sustain their survival and function. This metabolic dependency reveals new vulnerabilities that can be exploited for cancer therapy. In this review, we integrate fundamental concepts of lipid metabolism with recent mechanistic discoveries that define how lipids shape cellular behaviours within the TME, emphasizing the dual roles of lipids as both metabolic substrates and signalling mediators. We also highlight emerging evidence demonstrating that dietary lipid composition - beyond total fat intake - profoundly influences tumour progression and anti-tumour immunity. Together, these insights position lipid metabolism as a critical regulator of tumour biology and an attractive target for next-generation cancer therapies.
Choong-Hyun Koh, Y. Lee, Il-Kyu Kim et al.· Experimental and Molecular M...· 0 citations
: Gastric cancer (GC) remains a leading cause of global cancer mortality, with progression and therapy resistance heavily influenced by the dynamic tumor microenvironment (TME). Despite advances in surgical techniques, chemotherapy, targeted therapy, and immunotherapy, overall survival for advanced disease remains poor, underscoring the need for a deeper understanding of resistance mechanisms. A hallmark of the TME is metabolic reprogramming, which sustains tumor growth and actively shapes an immunosuppressive landscape. This review aims to detail the coordinated metabolic adaptations of GC cells, cancer-associated fibroblasts (CAFs), and immune cells within the TME, focusing on nutrient competition, immunosuppressive metabolite accumulation, and dysregulated lipid metabolism. We analyze how glucose depletion, lactate accumulation, and amino acid deprivation establish a hostile metabolic niche that impairs cytotoxic T lymphocyte (CTL) function while paradoxically supporting regulatory T cells (Tregs), M2-like tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs). We examine four major immunosuppressive metabolic pathways, lactate, adenosine, tryptophan-kynurenine, and arginine and demonstrate their convergence on immune checkpoint upregulation, forming an integrated metabolic-immune checkpoint axis. These pathways establish a self-reinforcing immunosuppressive circuit that drives T cell exhaustion and limits immune checkpoint blockade efficacy. We highlight emerging therapeutic strategies targeting this crosstalk, including inhibitors of glycolysis, glutaminolysis, indoleamine 2,3-dioxygenase 1 (IDO1), and adenosine signaling, often combined with immunotherapy. The metabolic supply-demand mismatch explains why certain interventions can revive effector cells while potentially harming other cell types. Finally, we discuss challenges and future directions, emphasizing the need for spatially resolved metabolic profiling, biomarker-driven patient stratification, and personalized therapies to overcome metabolic immunosuppression and improve clinical outcomes in GC.
Xiangyang Wang, Ying Wu, Yutong Fu et al.· Oncology Research· 0 citations
It is identified that lymph node metastases in high-risk neuroblastomas display distinctive cellular heterogeneity and plasticity, marked by mesenchymal-like and stem-like states and heightened epithelial-to-mesenchymal transition activity compared to primary adrenal tumors.
Laiman N. Wu, Janet L. Oblinger, Da-Zhuan Xin et al.· Science Advances· 0 citations
