Aug 2026· Bioessays· Vol 48· 0 citations· 148 references
Medicine
TL;DR
Tumor evolution, from premalignant lesions to metastasis, is increasingly recognized as shaped by continuous interplay between tumor cells metabolism and their microenvironment, generating adaptive niches that sustain tumor progression and metastasis.
Abstract
Tumor evolution, from premalignant lesions to metastasis, is increasingly recognized as shaped by continuous interplay between tumor cells metabolism and their microenvironment. During tumor initiation, major oncogenic pathways drive early metabolic reprogramming of lipid, amino acid, and energy pathways to promote cell competition and clonal expansion. These metabolic changes reciprocally shape the tumor microenvironment (TME) through metabolite fluxes, extracellular matrix remodeling, and immune reprogramming, generating adaptive niches that sustain tumor progression and metastasis. Cancer cell metabolic adaptability becomes even more crucial to survive dissemination and adapt to a new, distant microenvironment.
miRNAs are short RNA transcripts that modulate gene expression after transcription and have emerged as pivotal regulators of cancer biology. A subset, termed oncomiRNAs, functions as oncogenes or tumor suppressors, influencing key cellular events such as cell growth, programmed cell death, neovascularization, tissue invasion, and metastatic spread. Dysregulation of these miRNAs drives tumor initiation and progression, underscoring their role in cancer evolution. Traditionally, studies have relied on bulk tissue analyses, overlooking the profound spatiotemporal heterogeneity of oncomiRNA expression, including variations across tumor regions, metastatic sites, disease stages, and during treatment.
T. Jeethy, Ram Muralee, Muralee Damodaran· Cancer Reports· 0 citations
ABSTRACT
Tumor metabolic reprogramming is a hallmark of cancer and is driven not only by intrinsic mechanisms of tumor cells but also by dynamic interactions between the local tumor microenvironment (TME) and the host macroenvironment. This review systematically elaborates on the central role of "tumor-host" metabolic crosstalk in reshaping both the TME and the broader host macroenvironment. In the TME, hypoxia, nutrient deprivation, metabolic waste accumulation, and metabolic interactions among immune and stromal cells collectively facilitate tumor adaptation to harsh conditions and drive tumor progression. Concurrently, host macroenvironmental factors, including the gut microbiota and its metabolites, adipose tissue, systemic chronic inflammation, and hormonal imbalances, remotely regulate tumor initiation and development through multiple mechanisms. We further summarize emerging therapeutic strategies targeting metabolic pathways and emphasize the future need to break down boundaries between microenvironments and macroenvironments, suggesting the need for multiscale metabolic interventions to improve cancer treatment efficacy.
Yi Zhang, Caixia Suo, Linchong Sun· Chinese Medical Journal· 0 citations
The tumor microenvironment (TME) refers to the non-malignant cellular and stromal components present within tumors, which play critical roles in cancer initiation, progression, metastasis, and therapeutic response. Among the diverse cellular constituents of the TME, cancer-associated fibroblasts (CAFs) represent a key stromal cell population that is primarily involved in the formation and remodeling of the tumor-associated extracellular matrix (ECM), thereby influencing tumor progression through matrix remodeling, immune modulation, angiogenesis, and metabolic support. In addition, tumor cells undergo metabolic reprogramming to adapt to the hostile conditions of hypoxia and nutrient deprivation within the TME. CAFs may participate in this process by regulating tumor cell metabolism and stromal metabolic crosstalk, thereby contributing to energy supply and biosynthetic support. However, CAFs do not constitute a functionally uniform pro-tumorigenic cell population, as distinct CAF subtypes may exert either tumor-promoting or tumor-suppressive effects depending on tumor type, disease stage, and microenvironmental context. This review aims to systematically summarize the major mechanisms underlying metabolic reprogramming in CAFs, analyze their functional heterogeneity and associated controversies, and further explore targeted therapeutic strategies based on the metabolic characteristics of CAFs.
Tumor metastasis is the leading cause of cancer-related deaths. It depends not only on the intrinsic properties of cancer cells but also on their active shaping of the tumor microenvironment. Recent studies have identified mitochondrial transfer(MT) as a key mechanism underlying this tumor–microenvironment crosstalk. Beyond serving as a simple metabolic rescue pathway, MT functions as an intercellular reprogramming process that promotes metastatic progression. In this Review, we propose that MT acts as a tripartite educator during metastasis by driving three coordinated programs: metabolic licensing, immune rewiring, and stromal remodeling. Metabolic licensing enhances the survival and invasive capacity of cancer cells. Immune rewiring helps tumor cells evade immune surveillance. Stromal remodeling reprograms the tumor microenvironment into a permissive niche that supports tumor establishment. We summarize current evidence supporting each of these three programs and discuss emerging therapeutic strategies aimed at either blocking pathological MT or exploiting it for antitumor intervention.
Y. Duan, Anshu Li, Xun Hu et al.· Frontiers in Immunology· 0 citations
This review comprehensively examines the cellular and acellular architecture of the TME, emphasizing its spatial organization, metabolic reprogramming, mechanical properties, and immunological regulation across diverse tumor types.
R. Latif, Taufiq Nawaz· Critical reviews in oncology...· 0 citations
The tumor microenvironment (TME) is a dynamic and complex system comprising immune cells, stromal cells, blood vessels, and the extracellular matrix. The cellular and molecular elements can be different among cancer types, but they appear to be crucial for tumor initiation, survival, invasion, and metastasis. During early tumor development, cancer cells create a bidirectional relationship with TME components that allows them to evade immune detection, resist apoptotic processes, and promote angiogenesis and metastasis. Traditionally, cancer progression has been attributed simply to the sequential accumulation of genetic mutations. However, evidence is growing that epigenetic alterations, such as DNA methylation and hydroxymethylation, histone modifications, and microRNA dysregulation, are also important contributors to tumorigenesis. These epigenetic alterations also regulate critical signaling pathways related to apoptosis, autophagy, and cellular differentiation, which have implications for the emergence of aggressive cancer stem-like cells and further metastasis. The recognition of epigenetic regulatory mechanisms has also led to new therapeutic options. Epigenetic drugs, including DNA methyltransferase and histone deacetylase inhibitors, have been shown to reverse the expression of tumor suppressor genes, enhance the efficacy of conventional therapies, block the development of cancer progenitor cells, and reduce recurrence rates. Recognizing epigenetic dysregulation as a hallmark of cancer represents an opportunity to create new biomarkers and targeted treatments. Despite significant advances in surgery, chemotherapy, and radiotherapy, most standard treatments lack precision and typically have significant side effects. The movement toward immunotherapy, targeted therapy, and personalized medicine has allowed for more precise, less invasive, and more tolerable treatment regimens. At the same time, there has been an increasing recognition of the role of mitochondrial dynamics (such as fission, fusion, and mitophagy) as important regulators of tumor metabolism, drug resistance, and apoptosis. Although their clinical significance is still being fully explored, mitochondrial biomarkers and mitochondrial-targeted therapies present diagnostic and therapeutic value. Collectively, the degree to which the TME is responsive to different treatment modalities, the contribution of epigenetics, and the coordinated regulation of mitochondrial dynamics may contribute to a more informed theranostic application toward improving cancer diagnosis, treatment, and patient survival.
