It is argued that drug resistance is critically shaped by cancer cell plasticity, which varies widely among patients and contributes to heterogeneous therapeutic efficacy, and a next‐generation precision oncology paradigm integrating stratified diagnosis, rational combination intervention, and adaptive monitoring is proposed.
Abstract
Tumor heterogeneity creates selective pressures and ecological niches that enable cancer cell plasticity; conversely, plasticity continuously generates and reshapes heterogeneity. Together, these processes drive tumor progression, therapeutic resistance, recurrence, and divergent clinical outcomes, thereby limiting the durability of precision oncology. In this Review, we synthesize recent advances in our understanding tumor heterogeneity and cancer cell plasticity across spatial, temporal, and molecular scales, and discuss how the tumor microenvironment regulates plasticity through physical, chemical, and biological cues. We further outline three fundamental challenges for precision therapy, namely, target loss, bypass pathway activation, and adaptive cell‐state transitions, and argue that drug resistance is critically shaped by cancer cell plasticity, which varies widely among patients and contributes to heterogeneous therapeutic efficacy. Building on this framework, we propose a next‐generation precision‐oncology paradigm integrating stratified diagnosis, rational combination intervention, and adaptive monitoring. Finally, we discuss how the integration of single‐cell and spatial multiomics, together with artificial intelligence, could enable the development of “digital twin” tumor models to guide individualized therapeutic decision‐making. Collectively, this review provides an integrated conceptual foundation and practical roadmap for overcoming key bottlenecks in precision oncology driven by tumor heterogeneity and cancer cell plasticity.
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
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
A particular focus on the bidirectional interplay between CSCs and the tumor immune microenvironment is focused on, which may provide a conceptual framework for the development of more rational combination strategies, although their clinical benefit remains to be validated.
Jingyu Tan, Tao Wen, Jian Liu et al.· Journal of Hematology & Onco...· 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
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