Interconnected roles of cellular senescence and the immune microenvironment in tumor progression: from pan-cancer mechanisms to glioblastoma implications
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, to provide a new theoretical foundation for next-generation precision cancer immunotherapy.
Abstract
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.
It is proposed that integrating precise editing, in vivo screening, single-cell multi-omics, and emerging artificial intelligence (AI)-assisted design may provide information and a design basis for future combined strategies that simultaneously target vulnerabilities in senescent cells and malignant populations.
Bo Fan, Aiwei Wu, Xue Pan et al.· Ageing and Cancer Research &...· 0 citations
Cellular senescence plays a complex and crucial dual role in ovarian cancer treatment: it serves as both an important tumor suppression mechanism and a potential driver of drug resistance and recurrence. This review systematically examines the intricate regulatory network of cellular senescence, encompassing multiple pathways including telomere dysfunction, DNA damage response, epigenetic remodeling, hormone signaling, and metabolic reprogramming. Studies have demonstrated that core therapeutic modalities, such as platinum-based chemotherapy, PARP inhibitors, and CDK4/6 inhibitors, can exert anti-tumor effects by inducing cellular senescence; however, their efficacy is significantly influenced by the senescence-associated secretory phenotype (SASP). Specific SASP components can activate immune surveillance, whereas others promote tumor progression, acquisition of stem cell-like characteristics, and therapeutic resistance. It is this “anti-tumor versus pro-tumor” paradox that renders senescent cells a critical variable determining treatment outcomes. In light of this, emerging strategies aim to precisely modulate the senescence process, including the use of epigenetic drugs to induce senescence, targeting metabolic vulnerabilities to eliminate senescent cells, and intervening in deleterious SASP to improve the tumor microenvironment. Integrating such strategies with conventional therapies holds promise for overcoming the resistance bottleneck in ovarian cancer and opening new avenues for improving patient prognosis.
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.
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
Cellular senescence is a permanent state of growth arrest that develops when cells encounter various forms of
physiological or pathological stress. Although senescence initially functions as a protective mechanism by preventing the
proliferation of damaged cells, persistent senescent cells can alter the surrounding tissue environment through the release
of bioactive molecules collectively known as the senescence-associated secretory phenotype (SASP). These secretions may
promote chronic inflammation, tumor progression, metastasis, and resistance to anticancer therapy. Consequently, cellular
senescence has emerged as both a biological barrier to cancer and a promising therapeutic target. Recent advances have led
to the development of strategies that either induce senescence in malignant cells or selectively eliminate harmful senescent
cells using senolytic agents while suppressing detrimental SASP signaling through senomorphic therapies. In addition,
combining senescence-targeted interventions with chemotherapy, radiotherapy, immunotherapy, and molecularly targeted
therapies offers new opportunities to improve treatment efficacy and reduce disease recurrence. This review summarizes
the biological mechanisms regulating cellular senescence, highlights its contrasting roles in cancer development, discusses
emerging therapeutic approaches, and outlines current challenges and future directions for translating senescence-based
therapies into clinical oncology.
Awateef Fatima, Saba Yousuf· International Journal of Inn...· 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
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