Background: Exendin-4 (Ex-4), a stable glucagon-like peptide-1 receptor (GLP-1R) agonist, has transcended its initial role as a glycemic regulator to become a potent mediator of cellular inflammation. This review synthesizes the molecular crosstalk between Ex-4 and tissue-specific inflammatory environments, emphasizing its therapeutic trajectory. Summary: At the cellular level, Ex-4 exerts anti-inflammatory effects primarily through the inhibition of the NF-κB and NLRP3 inflammasome pathways and the activation of the SIRT1/AMPK axis. In the central nervous system, it facilitates a phenotypic shift from pro-inflammatory M1 to reparative M2 microglia. In peripheral tissues, it attenuates fibrosis via TGF-β/Smad suppression and restores airway homeostasis through the PKA-PPARγ-FOXA2 pathway. While there were signaled challenges in motor-score endpoints for Parkinson’s disease, the peptide shows robust efficacy in treating Idiopathic Intracranial Hypertension (IIH) and polycystic ovary syndrome (PCOS). Conclusion: Exendin-4 remains a cornerstone of metabolic-inflammatory research. Future therapeutic success likely hinges on the development of "smart" delivery systems-such as ligand-functionalized nanoparticles and sustained-release hydrogels-to optimize bioavailability and minimize systemic side effects (Figure 1).

Background: Advancing age is accompanied by a progressive accumulation of senescent cells that drive chronic, low-grade inflammation-a state widely termed ‘inflammageing’. This persistent inflammatory milieu profoundly impairs adaptive immunity, blunting the very T-cell and B-cell responses upon which cancer vaccines depend. Senolytics, a class of pharmacological agents that selectively eliminate senescent cells, have emerged as a promising strategy, although direct evidence for improved cancer-vaccine outcomes in humans remains limited, to recalibrate immune homeostasis and potentially restore vaccine responsiveness in older patients. Objective: This systematic review synthesises evidence on the mechanistic and clinical relationships between cellular senescence, Senescence-Associated Secretory Phenotype (SASP)-driven immunosuppression and cancer vaccine efficacy in older adults and critically examines whether senolytic preconditioning can improve vaccine outcomes. Methods: A systematic search of PubMed, Scopus, EMBASE, Web of Science and ClinicalTrials.gov was conducted from inception to March 2026 following PRISMA 2020 guidelines. Studies examining cellular senescence, SASP, immune senescence, senolytics (including dasatinib, quercetin, navitoclax, fisetin, ABT-263 and related agents) and cancer vaccination in aged models or human subjects were included. Quality appraisal used the Newcastle-Ottawa Scale and GRADE framework. A total of 2,847 records were identified; after removal of duplicates, 2,163 records were screened and 54 studies met full inclusion criteria. Results: Senescent cells were found to exert multi-layered suppression on anti-tumour immunity, including downregulation of T-cell receptor signalling, promotion of regulatory T cells and impairment of dendritic cell maturation-all mediated largely through SASP-derived interleukin-6 (IL-6), IL-1β, tumour necrosis factor-alpha (TNF-α) and prostaglandin E2 (PGE2). Senolytic treatment in murine models restored vaccine-induced CD8+ T-cell expansion and tumour rejection. The dasatinib-plus-quercetin (D+Q) combination demonstrated the most reproducible clearance of p16INK4a+ and p21CIP1+ senescent cells in cell-based and murine models; corroborating evidence from human clinical studies remains preliminary. Emerging clinical data from early-phase trials confirm safety in older adults and biomarker evidence supports transient SASP reduction following senolytic dosing. Conclusion: The available body of evidence, although predominantly preclinical, offers strong biological plausibility-as distinct from demonstrated clinical efficacy-for using senolytics as immunological primers before cancer vaccination in older adults. Well-designed clinical trials incorporating senolytic preconditioning windows prior to vaccine administration are urgently needed to translate these findings into practice.