2026· Ageing and Cancer Research & Treatment· 0 citations
TL;DR
A conceptual framework for understanding how ageing progressively modulates tumor dormancy is provided and potential strategies to prevent late metastatic recurrence are highlighted.
Abstract
Cancer recurrence remains a leading cause of mortality in patients with solid tumors. Early disseminated tumor cells (DTCs), which seed distant organs during the initial stage of tumor progression, are widely recognized as an important source of late metastatic relapse. Tumor cell dormancy, a reversible but prolonged non-proliferative state, enables DTCs to survive in metastatic tissues for years or even decades before re-entering the cell cycle and giving rise to overt metastases. Accumulating evidence indicates that dormancy is regulated by both cell-intrinsic mechanisms, such as epigenetic reprogramming and metabolic adaptation, and extrinsic cues from the tissue microenvironment. Among these extrinsic regulators, ageing has emerged as a critical determinant of DTC fate by profoundly remodeling tissue microenvironments through cellular senescence, chronic inflammation, extracellular matrix (ECM) remodeling, vascular dysfunction, stromal metabolic rewiring, and immune dysregulation. These ageing-associated alterations progressively erode dormancy-supportive niches, thereby leading to metastatic reactivation. In this Review, we summarize the molecular mechanisms governing tumor dormancy and discuss how ageing-associated microenvironmental remodeling contributes to the reactivation of dormant DTCs. We highlight the roles of the senescence-associated secretory phenotype (SASP), ECM remodeling, vascular deterioration, and organ-specific stromal ageing in regulating the maintenance and exit of tumor dormancy. We also discuss emerging translational opportunities, including dormancy-reinforcing therapies, senolytic strategies, liquid biopsy-based surveillance, and advanced experimental platforms such as single-cell and spatial technologies. Collectively, this Review provides a conceptual framework for understanding how ageing progressively modulates tumor dormancy and highlights potential strategies to prevent late metastatic recurrence.
Tumor recurrence represents a significant challenge in the field of tumor therapy, severely affecting patients' survival rates and quality of life. Even after standard treatments, many patients still experience tumor recurrence. Traditional radiotherapy, chemotherapy, and targeted therapies can induce tumor cell senescence to suppress tumor growth and dissemination. However, recent studies have shown that therapy-induced senescent tumor cells can re-enter the cell cycle, acting as a key driver of tumor recurrence. Consequently, senescent tumor cells have emerged as a pivotal focus for unraveling the mechanisms underlying tumor recurrence. This review systematically elucidates the multidimensional molecular regulatory networks through which senescent tumor cells promote tumor recurrence, encompassing key processes such as cell cycle reactivation mechanisms, epithelial-mesenchymal transition (EMT), acquisition of stemness phenotypes, formation of polyploid giant cancer cells (PGCCs), fate transition from senescence to pyroptosis, and remodeling of the immune microenvironment. Additionally, it summarizes the latest advances in targeted interventions against senescent tumor cells, including senolytics-mediated clearance of senescent cells and senomorphic modulation of the senescence-associated secretory phenotype (SASP). Furthermore, we propose that, guided by the molecular mechanisms underlying senescent tumor cell-mediated recurrence, the integration of multi-omics analyses to precisely delineate the therapeutic window, combined with artificial intelligence-driven drug screening, holds promise for developing more specific senolytic agents, thereby offering innovative strategies to improve recurrence control rates following cancer therapy.
A G0 persister-like state with reduced copy number alteration burden and hallmarks of dormancy is uncovered, characterised by transcriptional reprogramming of stress response pathways and increased epithelial-mesenchymal plasticity.
Cenk Celik, William A. Weston, Thais de Moraes-Lacerda et al.· Genome Medicine· 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
Cellular senescence is an irreversible cell state induced by diverse stressors, characterized by permanent cell cycle arrest coupled with sustained metabolic activity. In the context of tumor evolution, senescence exhibits remarkable complexity and dynamism: it functions not only as an early tumor-suppressive barrier that blocks malignant transformation but also recruits and reprograms immune cells through the senescence-associated secretory phenotype (SASP), thereby constructing a distinctive tumor microenvironment (TME). Concurrently, the status of the immune system, including the efficacy of immunosurveillance and the occurrence of local immune exhaustion, reciprocally determines the ultimate fate of senescent cells and governs the transition between their tumor-suppressive and tumor-promoting effects. This dynamic tripartite regulatory network comprising senescence, immunity, and the tumor constitutes the core framework for understanding tumor heterogeneity and drug resistance mechanisms. Advances in single-cell and spatial multi-omics technologies have provided unprecedented precision for dissecting the spatiotemporal evolution of this network. Current efforts to integrate senescence-targeted interventions, such as combinatorial “induce-modulate-eliminate” strategies, with modern immunotherapy show immense potential, although precisely breaching physical barriers and eradicating highly invasive senescent clones remain formidable challenges. This review systematically examines the molecular mechanisms of cellular senescence, with emphasis on the intrinsic logic governing bidirectional remodeling between senescent cells and the immune microenvironment. Glioblastoma (GBM) serves as the focal disease model throughout, providing in-depth analysis of how these mechanisms manifest within a highly immune-privileged ecosystem and their therapeutic implications. By dissecting the interplay between pan-cancer mechanisms and the GBM-specific microenvironment, this review aims to provide a new theoretical foundation for next-generation precision cancer immunotherapy.
Wenwen Zhao, Pengfei Zhang, Li-Xin Li et al.· Cell Death Discovery· 0 citations
Breast cancer remains the most frequently diagnosed malignancy and a leading cause of cancer-related mortality among women worldwide. While immune checkpoint inhibitors have transformed treatment for a subset of patients, durable responses remain limited, in part because the tumor immune microenvironment is profoundly shaped by age-associated immune decline—termed immunosenescence. In this review, we critically synthesize how tumor immunosenescence may contribute to breast cancer progression and therapeutic resistance, distinguishing correlative observations from mechanistically established relationships. We examine T cell senescence and exhaustion as mechanistically separable states with distinct therapeutic implications, and evaluate the roles of cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) as orchestrators of immunosenescence through SASP production, immune exclusion, and metabolic remodeling. We discuss subtype-specific immunosenescence signatures (TNBC, HER2+, HR+), hormonal and menopausal influences, stage-dependent immune alterations, and BRCA-associated susceptibility. The senescence-associated secretory phenotype (SASP)—comprising IL-6, IL-8, TGF-β, and matrix metalloproteinases—serves as a central mediator linking cellular senescence to immune evasion and metastatic dissemination, though much of the evidence derives from preclinical models. Therapy-induced senescence following chemotherapy and radiotherapy may paradoxically drive relapse through SASP-mediated immunomodulation, a hypothesis that lacks prospective clinical validation. We review clinical evidence that aging is associated with diminished interferon signaling, reduced tumor-infiltrating lymphocyte density, and altered checkpoint blockade efficacy in some but not all studies, acknowledging substantial inter-patient heterogeneity. We highlight recent advances in single-cell and spatial profiling technologies and discuss challenges in biomarker standardization and clinical implementation. Finally, we evaluate emerging interventions—senolytics (navitoclax, dasatinib plus quercetin, fisetin), senomorphics, metabolic rescue via NAD+ repletion, STING agonists, and rational senotherapy-immunotherapy combinations—emphasizing that most remain at preclinical or early clinical stages. We conclude that targeting tumor immunosenescence represents a promising but incompletely validated therapeutic axis for enhancing anti-tumor immunity in breast cancer.
Qing Lei, Xuejun Guo· Frontiers in Oncology· 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