The senescence-immune axis as a target for combining immunotherapy and senotherapy.

Abstract

Cellular senescence and immune dysfunction intersect as central biological processes shaping disease progression and therapeutic responses across ageing-related pathologies. Rather than acting independently, senescent cells (SnCs) and immune cells engage in a dynamic and bidirectional crosstalk that influences immune surveillance, inflammatory signaling, and tissue remodeling. This review focuses on the molecular and cellular mechanisms through which SnCs modulate immune composition and function, emphasizing immune checkpoint ligands, stress-associated surface molecules, and senescence-associated transcriptional programs governing senescence-associated secretory phenotype (SASP) expression. We further examine how immune-targeted therapies can, in turn, remodel senescent niches by promoting immune-mediated clearance or altering senescence-associated phenotypes. Integrating evidence from cancer to metabolic and chronic inflammatory diseases, we discuss how senotherapies reshape immune landscapes and how immunotherapies impact senescent cell burden and function. Building on these mechanistic insights, we propose that the senescence-immune axis constitutes a tractable therapeutic vulnerability that can be exploited through rational combination strategies. Finally, we outline five conceptual frameworks and biomarker-guided trial archetypes for integrating senotherapies and immunotherapies in a bidirectional crosstalk, aiming to enhance therapeutic efficacy while mitigating ageing- and treatment-associated toxicities. By reframing senescence and immunity as interconnected therapeutic targets, this review provides a mechanistic foundation for next-generation combinatorial interventions across ageing-associated diseases.