An Inflammaging-Related SASP and NLRP3 Signature Predicts Poor Prognosis and Metastasis in Elderly Cancer Patients

Aging is a complex, progressive, and irreversible biological process characterized by profound structural and functional declines [1]. Central to aging and its associated pathologies is “inflammaging”, a systemic, low-grade chronic inflammation [2]. A primary driver of this phenomenon is the Senescence-Associated Secretory Phenotype (SASP), a pro-inflammatory secretome released by cells undergoing replicative senescence. By compromising cellular homeostasis, SASP impairs the body’s ability to adapt to environmental stressors [3]. Consequently, this persistent chronic inflammation acts as a key driver in the pathogenesis of major age-related conditions, including neurodegenerative disorders, cardiovascular diseases, and cancer [4-6]. In this study, we evaluated the SASP and inflammatory secretory profiles in the serum of a cohort of 110 cancer patients aged over 65 years. We analyzed these profiles in relation to various comorbidities and assessed their overall impact on patient survival. Serum concentrations (pg/ml) of specific cytokines (CCL2, IL-1β, MMP-3, CXCL10, IL-6, TK1, and TNF-α) were quantified using a custom Luminex multiplex assay on the Bio-Plex 200 platform, while NLRP3 levels were determined via a commercial ELISA kit. Within our cohort, IL-6 and CXCL10 levels were significantly higher than those of IL-1β and TNF-α. Expression increased for the progression markers MMP-3 (involved in tissue remodeling and metastasis), CCL2 (MCP-1), and TK1, too. Additionally, a significant overexpression of NLRP3 was detected. Biomarker levels significantly correlated with specific patient comorbidities. Specifically, metastasis at diagnosis correlated with TNF-α, TK1, IL-6, IL-1β and CCL2. Additionally, neurological disorders associated with TK1 and CXCL10, while cardiomyopathies correlated with IL-1β. Survival analysis showed that high expression of IL-6, TNF-α, TK1, CXCL10, CCL2, and NLRP3 significantly predicted poorer DFS (p < 0.05). Additionally, elevated IL-6 and CCL2 levels were strong predictors of shortened OS (p< 0.01). Multivariate analysis revealed that IL-6 and CCL2 acted as independent negative prognostic factors for DFS. Regarding OS, IL-6, CCL2, TK1, and NLRP3 all emerged as independent indicators of poor prognosis. In conclusion, chronic inflammation, driven by senescent cell signaling (IL-6, CCL2), accelerates cancer progression and metastasis, particularly in older patients. High levels of these markers, along with TK1 and NLRP3, independently predict shorter survival and increased mortality risk.