The Chaperone System at the Crossroads of Cancer and Cellular Senescence: Mechanisms and Therapeutic Horizons

As organisms age, their cells undergo a complex process of decline. Two interconnected phenomena at the heart of this biological deterioration are cellular senescence and the decline of the Chaperone System (CS). Together, these deteriorating processes determine that our bodies become less resilient over time. The CS of an organism encompasses all its molecular chaperones, co-chaperones, chaperone co-factors, and chaperone receptors and interactors. A few CS components belong to families of heat-shock proteins (Hsp). The CS has two types of functions, canonical and non-canonical with the former dedicated to maintaining protein homeostasis and the latter pertaining to a variety of other cellular processes. The CS is typically considered cytoprotective, but it can also be part of pathogenic mechanisms that cause diseases, the chaperonopathies. Ageing includes mechanisms that involve “sick” chaperones, namely ageing can be considered a chaperonopathy in which several components of the CS malfunction due to the damage caused by ageing on the CS components themselves. Some chaperonopathies are caused by normal chaperones that get involved in pathogenic pathways and thus they turn against their own organism. Consequently, these chaperonopathies are grouped as chaperonopathies by mistake or collaborationism (chaperones collaborate with the enemy, e.g., carcinogenesis, instead of combating it as expected of them).Aging and cancer are deeply intertwined: advancing age is the single largest risk factor for most malignancies, and many of the molecular processes that drive aging - including cellular senescence, autophagy dysfunction, mitochondrial decay, and abnormalities of protein homeostasis – may also be involved in tumor initiation, progression, and response to therapy. Cellular senescence sits at the heart of this interplay. As a permanent state of cell cycle arrest triggered by cellular stress, cell senescence acts as a barrier against tumorigenesis early in life, yet the accumulation of senescent cells with age fuels tissue dysfunction, chronic inflammation, and a pro-tumorigenic microenvironment that shorten health span. Cellular senescence therefore acts as a double-edged sword (antagonistic pleiotropy) throughout an individual's life, requiring better knowledge than currently available to be governed for our benefit. The CS (for example some Hsps) has emerged as a key regulator at this aging–cancer interface, with multifaceted roles in maintaining protein homeostasis, modulating stress responses, coordinating autophagy, and balancing cellular longevity with malignant transformation. How these chaperones shape the aging trajectory and influence cancer risk, progression, and treatment outcomes in older individuals remains incompletely understood.Recent studies show that depletion of specific Hsps accelerates cellular senescence and disrupts protein homeostasis, while their overexpression can delay senescence, modulate autophagic flux, and alter tumorigenic potential. These findings point to complex, context-dependent roles for CS components in determining cellular fate between survival, senescence, and transformation - with direct implications for age-related cancer susceptibility, metastasis, relapses, and therapy-induced aging. The field is now moving toward dissecting these dual functions to determine when the CS acts as protector of genomic and proteomic integrity that support healthy aging, or as enabler of cancer cell resilience that accelerate decline. Despite growing research interest, a comprehensive synthesis of the molecular interplay between the CS, hallmarks of aging such as senescence and autophagy, and cancer is still lacking, limiting our capacity to target these pathways to extend health span and improve outcomes in older patients with cancer.This Research Topic aims to deepen our understanding of the role of the CS, particularly Hsps, in the molecular mechanisms of aging - with a focus on cellular senescence - and their contribution to cancer across the life course. It seeks to clarify whether these proteins act as “friends” that maintain proteomic stability and support healthy aging, or “foes” that drive tumor progression and therapy resistance in aged tissues (chaperonopathies by mistake or collaborationism). Ultimately, the age-related breakdown of the CS acts as a molecular tipping point that bridges organismal aging with oncogenesis. By consolidating emerging evidence, this Research Topic intends to identify key regulatory pathways, uncover therapeutic targets, and highlight the molecular determinants that tip the balance between protective and harmful outcomes across the aging–cancer continuum, with translational relevance to cancer survivorship, resilience, and health span. By connecting the fields of chaperone biology, senescence, and oncology, this Research Topic will provide a definitive framework for therapies that do not just treat disease, but actively preserve host resilience and functional health span.To gather further insights into the dual roles of CS components in aging, cellular senescence, and cancer, we welcome articles addressing, but not limited to, the following themes:- Cellular senescence and other hallmarks of aging in cancer initiation, progression, metastasis, and relapse- Molecular mechanisms underlying CS-mediated regulation of senescence and aging-related pathways - CS in the regulation of autophagy, protein homeostasis, and cellular longevity in the context of cancer- Differential expression and functional diversity of CS components in tumorigenesis, aging tissues, and senescence- Interplay between CS, age-related decline of protein homeostasis, and oncogenic signaling- Therapeutic potential of modulating defined CS components, autophagy, or senescence pathways to improve health span and outcomes in age-related cancers- Impact of cancer therapeutics on CS function, accelerated aging, and senescence in survivors- In vitro, in vivo, and translational models exploring CS function at the aging–cancer interface- Identifying specific CS profiles, Hsp post-translational modifications, or senescent cell surface markers that can serve as predictive biomarkers for biological age, frailty, cancer susceptibility, or adverse treatment outcomes.- Utilizing transcriptomic, proteomic, and single-cell sequencing data to map the dynamic changes of the chaperone network across the aging–cancer continuum in various tissues and organ systems.- Possible applications of AI to elucidate the subtopics listed above and other still enigmatic aspects of senescence-CS-cancer Topic editors: Giusi Alberti, Antonella Marino Gammazza, Alberto J. L. Macario Source: https://www.frontiersin.org/research-topics/80881/the-chaperone-system-at-the-crossroads-of-cancer-and-cellular-senescence-mechanisms-and-therapeutic-horizons