Interconnected roles of cellular senescence and the immune microenvironment in tumor progression: from pan-cancer mechanisms to glioblastoma implications

Abstract

Cellular senescence is an irreversible cell state induced by diverse stressors, characterized by permanent cell cycle arrest coupled with sustained metabolic activity. In the context of tumor evolution, senescence exhibits remarkable complexity and dynamism: it functions not only as an early tumor-suppressive barrier that blocks malignant transformation but also recruits and reprograms immune cells through the senescence-associated secretory phenotype (SASP), thereby constructing a distinctive tumor microenvironment (TME). Concurrently, the status of the immune system, including the efficacy of immunosurveillance and the occurrence of local immune exhaustion, reciprocally determines the ultimate fate of senescent cells and governs the transition between their tumor-suppressive and tumor-promoting effects. This dynamic tripartite regulatory network comprising senescence, immunity, and the tumor constitutes the core framework for understanding tumor heterogeneity and drug resistance mechanisms. Advances in single-cell and spatial multi-omics technologies have provided unprecedented precision for dissecting the spatiotemporal evolution of this network. Current efforts to integrate senescence-targeted interventions, such as combinatorial “induce-modulate-eliminate” strategies, with modern immunotherapy show immense potential, although precisely breaching physical barriers and eradicating highly invasive senescent clones remain formidable challenges. This review systematically examines the molecular mechanisms of cellular senescence, with emphasis on the intrinsic logic governing bidirectional remodeling between senescent cells and the immune microenvironment. Glioblastoma (GBM) serves as the focal disease model throughout, providing in-depth analysis of how these mechanisms manifest within a highly immune-privileged ecosystem and their therapeutic implications. By dissecting the interplay between pan-cancer mechanisms and the GBM-specific microenvironment, this review aims to provide a new theoretical foundation for next-generation precision cancer immunotherapy.