“Immune senescence and dormant tumor cells: reconceptualizing breast cancer recurrence as an affliction of aging and chronic inflammation”

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Abstract
One of the most significant clinical challenges in breast cancer is late recurrence, especially in estrogen receptor-positive disease. The biochemical causes of long-term dormancy are still not fully understood, and conventional surveillance frequently lacks sufficient sensitivity to reliably predict relapse. The objectives of this review are to: (1) investigate the molecular connections among immunosenescence, chronic inflammation, and tumor dormancy; (2) critically assess new therapeutic and diagnostic strategies; and (3) pinpoint methodological and translational gaps for further investigation. By combining geroscience and oncologic biology, this narrative review critically summarizes contemporary research on immunological senescence, tumor dormancy, and chronic inflammation published between 2015 and 2025. For preclinical, translational, and clinical research, databases such as PubMed and Scopus were examined, with a focus on mechanistic insights, liquid biopsy technologies, and experimental therapy approaches. Using combinations of phrases like “breast cancer recurrence,” “tumor dormancy,” “immunosenescence,” “inflammaging,” “liquid biopsy,” and “senolytics,” a focused literature search was carried out across PubMed and Scopus for research published between January 2015 and September 2025. Original English-language studies, reviews, and meta-analyses that addressed the molecular, translational, or clinical aspects of immunological aging and dormancy met the inclusion criteria. When preclinical research was pertinent to human pathology, it was included. Non-peer-reviewed commentary, conference abstracts without complete data, and research unrelated to breast cancer were the exclusion criteria. Although causality has not been established, there is evidence that immunosenescence and inflammation may create suitable habitats for dormant micrometastases. While liquid biopsy platforms for detecting minimal residual disease (MRD) provide earlier relapse signals, they have questionable clinical usefulness, analytical limitations, and confounding issues related to clonal haematopoiesis. Senolytics, epigenetic modulators, and “awaken-and-kill” immunotherapies are examples of experimental approaches that show promise but also have unidentified hazards, such as off-target toxicity and unintentional acceleration of metastases. Crucially, the majority of mechanistic insights derive from studies in young murine models, which restricts their applicability to aging human populations. Equity issues remain poorly understood, particularly in environments with limited resources. Rethinking late recurrence as a chronic inflammation and aging ailment offers a unifying theory, but it must be interpreted carefully. Translation necessitates rigorous MRD-linked trial designs, prospective validation in diverse and elderly cohorts, and a methodical assessment of both safety and efficacy. Adopting these strategies too soon could backfire if limitations and confounders are not critically evaluated.

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