Jul 2026· Signal Transduction and Targeted Therapy· Vol 11· 0 citations· 475 references
Medicine
TL;DR
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.
Abstract
Tumor heterogeneity is a fundamental hallmark of cancer that drives progression, metastasis and therapeutic resistance. This diversity originates from persistent genomic instability, dynamic clonal evolution, and cancer stem cell plasticity, which are further amplified through complex crosstalk within the tumor microenvironment. While conventional therapies effectively eliminate certain tumor cell populations, residual resistant subclones frequently lead to disease relapse. Recent breakthroughs in single-cell multi-omics, spatial transcriptomics, and liquid biopsy now enable a comprehensive, multidimensional dissection of tumor heterogeneity across molecular, cellular, spatial, and temporal scales. These approaches reveal real-time dynamics of tumor evolution, providing new opportunities for therapeutic intervention. 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. We critically examine how these insights are informing novel therapeutic paradigms—including targeting clonal cooperative networks, modulating epigenetic plasticity and reprogramming metabolic adaptations. Finally, we outline future pathways toward precision medicine through the integration of multi-omics data and dynamic monitoring technologies. Ultimately, overcoming tumor heterogeneity necessitates reconceptualizing cancer not as a static collection of cells but as a dynamically evolving ecosystem.
Cancer is one of the leading causes of global morbidity and mortality and is characterized by its high heterogeneity, genomic instability and adaptive plasticity. Applying Darwin’s theory of evolution, the concept of tumor evolution has improved our understanding of the biological behavior of advanced cancer, while technological limitations have long left how to dynamically characterize the evolutionary process unsolved. In recent years, the development of high-throughput sequencing, single-cell and spatial omics, lineage tracing, computational modeling, and noninvasive biopsy technology has helped explain tumor heterogeneity and track the evolutionary trajectory of tumors, which has attracted widespread attention in tumor evolution. Here, we discuss the models and drivers of tumor evolution, focusing on how cancer cells adapt and evolve under multidimensional selective pressure, including the intracellular, extracellular, and exogenous levels. We further summarize key signaling pathways and molecular mechanisms involved in genomic instability, epigenetic regulation, metabolic reprogramming, tumor microenvironment remodeling, immune escape and therapy-induced selection. In addition, emerging therapeutic strategies guided by tumor evolution are also discussed, emphasizing that the identification of key genetic and epigenetic targets, together with dynamic monitoring of clonal changes, is crucial for overcoming treatment resistance and improving patient outcomes. By systematically summarizing the signaling pathways and molecular mechanisms underlying tumor evolution, this review aims to provide new targets and conceptual frameworks for promoting precision treatment strategies in oncology in the future.
Kun-Yu Zhang, Xiu-Zhi Zhu, Yuxin Yan et al.· Signal Transduction and Targ...· 1 citation
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
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
Current insights into the molecular mechanisms underlying TME remodeling are summarized, including ECM mechanotransduction, hypoxia-driven signaling, hypoxia-driven signaling, epigenetic regulation, metabolic reprogramming, and extracellular vesicle-mediated communication.
Xiaoying Li, Shuang Dai, Dan Cao et al.· Frontiers in Cell and Develo...· 0 citations
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.
Dr. Gopalaxmi Nath, Moumita Ghosh, Dr Shahid Ahmad Shergojry et al.· Genetics and Molecular Resea...· 0 citations
ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is among the most aggressive human malignancies and has an extremely poor prognosis. Its progression is largely driven by a highly complex and immunosuppressive tumor microenvironment (TME), highlighting the urgent need for a deeper understanding of its molecular mechanisms. Recent advances in single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) have provided unprecedented opportunities to dissect cellular heterogeneity, spatial organization, and gene expression dynamics within the TME. In this review, we summarize the major scRNA-seq and ST technologies and their unique strengths in cancer research and highlight their integrated applications in revealing PDAC heterogeneity, stromal–immune interactions, and mechanisms of therapeutic resistance. We further discuss how these approaches can inform biomarker discovery and guide the development of novel therapeutic strategies. Together, these findings suggest that integrated single-cell and spatial transcriptomics offers transformative potential to advance precision oncology and improve outcomes for patients with pancreatic cancer.
Mengting Luo, Feng Shen, Wanli Xu et al.· Cancer Biology & Therapy· 0 citations