Jul 2026· Genetics and Molecular Research· 0 citations· 11 references
TL;DR
The evidence demonstrates that growth factor signalling, inflammatory pathways, hypoxia, metabolic reprogramming, genetic and epigenetic alterations, and extracellular vesicle-mediated communication alter the tumour microenvironment, encouraging tumour growth, metastasis, immune escape, and resistance to immunotherapy, chemotherapy, radiation, and targeted treatment.
Abstract
Malignant cells, stromal cells, immunological populations, extracellular matrix elements, and other signalling chemicals make up the tumour microenvironment (TME), a dynamic and intricate ecology that controls cancer initiation, development, metastasis, and treatment response. There is growing evidence that the reciprocal interactions between tumour cells and the tumour microenvironment are critical in defining the course of the illness and the effectiveness of therapy. This review aims to recapitulate the molecular, genetic, epigenetic, and immunological determinants governing tumor microenvironment dynamics, emphasising their contributions to therapeutic resistance, the development of microenvironment-targeted therapy approaches, and the progression of cancer. A literature review was conducted using peer-reviewed articles published in high-impact scientific journals. Relevant studies addressing the molecular architecture of the tumor microenvironment, signaling pathways, immune regulation, tumor heterogeneity, therapeutic resistance, and an integrative picture of current knowledge was produced by critically analysing and synthesising developing technology. and future research directions. The evidence demonstrates that growth factor signalling, inflammatory pathways, hypoxia, metabolic reprogramming, genetic and epigenetic alterations, and extracellular vesicle-mediated communication alter the tumour microenvironment, encouraging tumour growth, metastasis, immune escape, and resistance to immunotherapy, chemotherapy, radiation, and targeted treatment. By enhancing biomarker identification and customised therapy decision making, emerging technologies including as single-cell multi-omics, spatial transcriptomics, artificial intelligence, organoid models, and liquid biopsy are boosting precision oncology. Targeting the tumor microenvironment alongside malignant cells offers significant opportunities to overcome therapeutic resistance and improve clinical outcomes. Integrating multi-omics technologies with precision medicine methods are anticipated to aid in the creation of individualised, long-lasting, and more potent cancer treatments.
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
This review synthesizes key advances in understanding tumor heterogeneity: from its cellular origins and molecular mechanisms to its multidimensional manifestation in the tumor microenvironment and from metastatic heterogeneity to the fundamental causes of treatment resistance.
Jianhong Zhang, Heng Li, S. Ru et al.· Signal Transduction and Targ...· 0 citations
Among the leading causes of cancer-related morbidity and mortality worldwide, breast
cancer presents fundamental challenges, such as tumor heterogeneity and therapeutic resistance. The
tumor microenvironment (TME), comprising stromal components, signaling molecules, immune
cells, and the extracellular matrix, has demonstrated a pivotal role in tumor progression, invasion, and
therapeutic response. In this review, we comprehensively summarize the state-of-the-art and novel
therapeutic strategies developed to reprogram the TME in breast cancer. From clinically established
treatments, such as endocrine therapy, antibody-drug conjugates, and HER2-targeted therapy, to
emerging agents, such as siRNA-mediated gene silencing, nanomedicine, and immunotherapy, each
class of therapeutic strategy, along with the corresponding clinical and preclinical outcomes, is detailed
by category. The evidence for and impact of TME heterogeneity and differences in molecular
subtypes on therapeutic efficiency are highlighted, and biomarker-guided patient stratification is further
emphasized to support precision therapy. Mechanistic challenges, such as immunosuppression,
ECM remodeling, and hypoxia-associated resistance, were analyzed, and mechanistic conflicts or
synergistic interactions between strategies were identified. Tumor microbiome modification and AIdriven
discovery of novel biomarkers are presented as emerging perspectives in TME-targeting therapy.
Despite significant advances, translation barriers, such as the lack of predictive biomarkers and
the divergence in therapeutic outcomes between patients and animal models, are critically reviewed
and discussed. The integration of TME-targeted and individualized therapeutic strategies may offer
promising prospects toward achieving durable clinical outcomes in breast cancer treatment.
P. Shankar, Gowthamarajan Kuppusamy, Apsara Unni et al.· Current Cancer Therapy Revie...· 0 citations
Tumor plasticity and microenvironmental heterogeneity are established as an integrated, evolving system that fuels metastasis and limits durable treatment responses.
G. Dagar, M. Dagar, Ashna Gupta et al.· MedComm· 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.
Background:
Apoptosis is a tightly regulated form of programmed cell death that is essential for tissue homeostasis, normal development, and tumour suppression. Although defective apoptotic signalling is a hallmark of cancer, accumulating evidence indicates that apoptosis may also paradoxically promote tumour progression through its effects on the tumour microenvironment (TME), giving rise to the concept of the "apoptosis paradox."
Objectives:
To critically review the dual role of apoptosis in cancer progression, with particular emphasis on its immunomodulatory, regenerative, and pro-tumorigenic functions within the TME, and to discuss the therapeutic implications of targeting apoptosis-associated pathways.
Methods:
A comprehensive narrative review of the contemporary literature was conducted using peer-reviewed studies addressing the molecular mechanisms of apoptosis, apoptosis-mediated remodelling of the TME, immune regulation, autophagy, angiogenesis, metastasis, therapeutic resistance, and emerging apoptosis-targeted cancer therapies.
Results:
Current evidence demonstrates that, beyond eliminating damaged or transformed cells, apoptotic tumour cells actively influence the TME by releasing bioactive mediators that regulate immune responses, promote pro-tumorigenic macrophage polarization, stimulate angiogenesis and tissue regeneration, and facilitate tumour growth, metastatic dissemination, and resistance to therapy. Furthermore, the intricate interplay between apoptosis, autophagy, and immune signalling highlights the context-dependent nature of programmed cell death in cancer biology, challenging the traditional view of apoptosis as solely tumour suppressive.
Conclusions:
Apoptosis exhibits a dualistic role in cancer, functioning as both a tumour-suppressive and tumour-promoting process depending on the biological context. A deeper understanding of apoptosis-mediated interactions within the TME may uncover novel therapeutic targets and support the development of precision-based strategies that improve treatment efficacy and clinical outcomes in patients with cancer.
D. Koner, Dr. Swagata Gayen, Dr. Sanjeet Kumar Das et al.· International journal of med...· 0 citations