Tumor evolution: signaling pathways, molecular mechanisms and therapeutic targets

Transforming Cancer Treatment: Integrative Strategies Targeting the Tumor Microenvironment through Biological Innovation and Artificial Intelligence.

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.

Tumor Plasticity and Microenvironmental Crosstalk as Drivers of Metastasis and Therapy Resistance

Tumor plasticity and microenvironmental heterogeneity are established as an integrated, evolving system that fuels metastasis and limits durable treatment responses.

Targeting tumor transition windows

Tumor heterogeneity and cellular plasticity are major drivers of therapeutic failure across many cancer types. While precision oncology has largely focused on static genomic alterations, growing evidence indicates that tumors behave as dynamic biological systems that continuously adapt during treatment. Tumor cell populations can transition between distinct functional states under therapeutic pressure, including transient drug-tolerant phenotypes that may precede stabilization of genetically or epigenetically resistant clones. These transitions are shaped by mechanisms such as epigenetic reprogramming, stress-response signaling, metabolic rewiring, and microenvironmental interactions. This review synthesizes findings from tumor plasticity, drug-tolerant persister biology, therapy-induced vulnerabilities, clonal evolution, and adaptive therapy to examine how temporal tumor dynamics influence treatment response. Emerging evidence suggests that some tumors may pass through short-lived phases of cellular instability during therapy in which molecular dependencies, stress-response programs, or adaptive survival states are altered before resistance becomes genetically or epigenetically stabilized. However, such transition states should be considered therapeutically actionable only when linked to functional evidence of altered drug sensitivity, pathway dependence, immune susceptibility, or clinical response. Advances in single-cell transcriptomics, epigenomic profiling, serial circulating tumor deoxyribonucleic acid (ctDNA)/cfDNA analysis, multi-omics integration, and dynamic imaging are enabling longitudinal monitoring of tumor state transitions and may facilitate identification of transient biological states preceding stable resistance. Integrating temporal tumor biology with therapeutic sequencing strategies, adaptive treatment schedules, and biomarker-guided monitoring may therefore help test whether specific adaptive states can be therapeutically exploited and may refine precision oncology approaches.

Dynamic tumor microenvironment remodeling in cancer therapy resistance: molecular mechanisms and translational opportunities

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.

Molecular cartography of breast cancer: decoding genomes, heterogeneity and the tumor microenvironment for personalized targeted therapeutics

Stemness plasticity in hepatocellular carcinoma: spatial niches and therapeutic implications.

Hepatocellular carcinoma (HCC) remains a major global health burden, with therapeutic resistance limiting the long-term efficacy of current treatments. Although cancer stem cell (CSC) models have been proposed to explain tumor initiation and relapse, strategies targeting marker-defined CSC populations have shown limited clinical benefit. Increasing evidence indicates that stemness in HCC is not a fixed cellular trait but a dynamic and reversible state that can be induced, maintained, and re-established under therapeutic pressure. This stemness plasticity is regulated by tumor-intrinsic signaling pathways, including TGF-β, YAP/TAZ, and Wnt/β-catenin, and stabilized by epigenetic and post-transcriptional mechanisms such as N6-methyladenosine (m6A) modification. In parallel, spatially organized tumor microenvironmental niches composed of cancer-associated fibroblasts, macrophages, and endothelial cells provide critical signals that support stem-like phenotypes and immune evasion. These interconnected mechanisms collectively contribute to therapeutic resistance and tumor progression. This review synthesizes current evidence linking stemness plasticity to spatial niche regulation and treatment failure in HCC, and outlines a therapeutic framework that integrates targeting of intracellular regulatory programs with disruption of microenvironmental support systems. We further discuss the implications of this framework for the development of combination strategies and dynamic biomarkers that better capture the context-dependent nature of stemness. Together, these insights support a shift from targeting static cell populations toward targeting the regulatory processes that govern tumor cell plasticity in HCC.