Aug 2026· Cells· Vol 15, pp. 1457· 0 citations· 160 references
Medicine
TL;DR
This review summarizes how SASP programs, Th17/Treg imbalance, IL-17/IL-23 signaling, myeloid remodeling, stromal aging, metabolic stress, and immune–stromal–epithelial crosstalk shape prostate cancer biology and discusses therapeutic implications.
Abstract
Highlights What are the main findings? Aging reshapes the prostate tumor microenvironment through cellular senescence, chronic inflammation, immune remodeling, stromal dysfunction, vascular aging, and metabolic stress. Senescence-associated secretory programs and immune-aging networks create an inflammaging niche that may influence prostate cancer progression, immune evasion, and therapy response. What are the implications of the main findings? Inflammaging should be considered an active biological context for prostate cancer progression, rather than merely a consequence of chronological aging. Age-appropriate models, biological-aging biomarkers, spatial profiling, and multi-omics approaches are needed to define and therapeutically target inflammaging-associated prostate cancer. Abstract Prostate cancer is common in older men, yet mechanisms linking aging to tumor progression remain incompletely defined. Beyond genetic alterations, aging reshapes the prostate microenvironment through cellular senescence, chronic low-grade inflammation, immune dysfunction, stromal remodeling, metabolic stress, and impaired tissue repair, collectively promoting inflammaging. This persistent inflammatory state may create a permissive niche for tumor initiation, progression, immune evasion, and treatment resistance. Senescent epithelial and stromal cells release cytokines, chemokines, growth factors, matrix-remodeling enzymes, and extracellular vesicles through the senescence-associated secretory phenotype (SASP). In parallel, immune aging alters T-cell subsets, myeloid cells, macrophages, and anti-tumor surveillance. This review summarizes how SASP programs, Th17/Treg imbalance, IL-17/IL-23 signaling, myeloid remodeling, stromal aging, metabolic stress, and immune–stromal–epithelial crosstalk shape prostate cancer biology. We further discuss therapeutic implications, including cytokine modulation, senescence-directed therapy, metabolic intervention, and biomarker-guided strategies. This review highlights key knowledge gaps and proposes a framework for age-aware prostate cancer research, biomarker development, and therapeutic strategies.
Prostate cancer is a typical age-associated malignancy, and increasing evidence suggests that age-related immune alterations play an important role in its initiation, progression, and therapeutic response. Immunosenescence, characterized by impaired immune surveillance, reduced effector-cell function, contraction of the naïve T-cell repertoire, and persistent low-grade inflammation, may contribute to the establishment of a tumor-permissive microenvironment in older patients. In prostate cancer, these changes are particularly relevant because the disease often develops in an immunologically “cold” and suppressive tumor milieu. In addition to systemic immune aging, cellular senescence and the senescence-associated secretory phenotype (SASP) further reshape the local microenvironment by promoting chronic inflammation, stromal remodeling, and immune dysfunction. Together, immunosenescence, inflammaging, and senescence-related signaling may facilitate tumor persistence, immune escape, and resistance to therapy. Emerging therapeutic strategies therefore extend beyond tumor-intrinsic targets and include optimization of immunotherapy, reprogramming of the tumor microenvironment, and targeting of senescent cells or SASP-related pathways. A deeper understanding of how aging-related immune dysfunction interacts with prostate cancer biology may help improve patient stratification and support the development of more individualized treatment strategies for older prostate cancer patients.
Juntao Guo, Ke Wu, Zheng Ma et al.· Frontiers in Immunology· 0 citations
Aging is a multifaceted biological process that profoundly influences cancer development and progression. As life expectancy increases, understanding the molecular links between aging and oncogenesis becomes crucial for developing targeted therapeutic interventions. This review explores key aging‐related mechanisms, including genomic instability, telomere attrition, cellular senescence, chronic inflammation (inflammaging), and immune system decline, all of which create a tumor‐permissive environment. The role of aging‐associated genes such as
p53
, sirtuins, telomerase reverse transcriptase (
TERT
), Werner syndrome protein (
WRN
) helicase, and ataxia‐telangiectasia‐mutated (ATM) in regulating both longevity and cancer susceptibility is also discussed. Furthermore, the concept of senescence‐associated secretory phenotype (SASP) is highlighted as a double‐edged sword in cancer progression, contributing to both tumor suppression and malignancy. Additionally, biomarkers of aging relevant to cancer detection and prognosis are examined. Finally, potential therapeutic strategies, including senolytics, anti‐inflammatory treatments, and immune‐modulating approaches, are considered promising avenues to mitigate cancer risk in aging populations. A deeper understanding of aging‐related molecular pathways will aid in the development of precision oncology strategies tailored to elderly cancer patients.
Anu Singh, Aroonima Misra, S. Zaheer· Aging and Cancer· 0 citations
Population aging is a major global health challenge and a principal risk factor for cancer. Aging does not simply increase mutational burden; it reshapes tissue homeostasis across genetic, epigenetic, metabolic, immune, and systemic dimensions. Genomic instability, epigenetic drift, mitochondrial dysfunction, and metabolic rewiring collectively establish a tumor-permissive landscape that enhances clonal diversification and lowers the threshold for malignant transformation. Concurrently, accumulation of senescent cells and the senescence-associated secretory phenotype (SASP) remodel the microenvironment, promote immune suppression, and weaken tumor surveillance, further exacerbated by immunosenescence and gut microbiota dysbiosis. Importantly, cancer progression feeds back to accelerate organismal aging. Tumor burden and therapy-induced stress destabilize hematopoietic and non-hematopoietic stem cell niches, disrupt systemic metabolic homeostasis, and induce neuroendocrine reprogramming, thereby amplifying multi-organ functional decline. Aging and cancer therefore constitute a bidirectional and self-reinforcing network rather than a linear cause-effect relationship. In this review, we synthesize mechanistic, clinical, and translational evidence defining the tumor-aging axis and discuss emerging strategies aimed at interrupting this pathogenic cycle.
Yuxin Wang, Guitong Lv, Xinyue Gao et al.· Frontiers in Immunology· 0 citations
Cellular senescence is a stress-response program that coordinates cell-autonomous growth arrest and non-cell autonomous remodeling of the tissue environment. Initially defined through its role in aging and tumor suppression, senescence is now recognized as a highly complex program shaped by cell-intrinsic and environmental factors. This complexity places senescence as a broad stress response mechanism operating at the intersection of metabolic dysfunction, chronic inflammation and tissue repair. Given its constant exposure to metabolic, inflammatory and toxic stress alongside its high regenerative demands, the liver is particularly prone to engage senescence as a protective mechanism to maintain tissue integrity. In this context, senescence exerts dual and often opposing effects. This review discusses the multifaceted roles of senescence along the liver disease trajectory, from its early protective functions in tissue repair to its later pathologic contributions to chronic liver disease and tumor progression, underscoring how cell type, stage of senescence program, disease stage and microenvironmental cues shape these divergent outcomes. We highlight the potential of emerging therapeutic interventions that modulate senescence, including pro-senescence, senolytic, senomorphic, and immune-modulating strategies. Advancing our understanding of the multifaceted roles of cellular senescence will be essential to translate this knowledge into therapies that selectively modulate senescent cell states, harnessing their beneficial effects while limiting their detrimental roles in chronic liver disease and cancer.
Efi Tsouri, Niovi Athanasopoulou, L. Akkari et al.· Seminars in Immunology· 0 citations
It is highlighted that future OA treatment may gradually shift from symptom-oriented management toward disease-modifying therapy based on the identification of immune endotypes, and further studies are required to validate the underlying molecular mechanisms, evaluate safety, and conduct clinical trials, thereby facilitating the clinical translation of immune reprogramming strategies for OA.
Tong Wang, Wei Jiang, Xingxu Chen et al.· Frontiers in Immunology· 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
