Therapy-Induced Senescence in Cancer: Mechanisms, Immune Interplay, and Therapeutic Strategies

Abstract

Therapy-induced senescence (TIS) has emerged as a pivotal mechanism in cancer therapy, exerting both tumor-suppressive and tumor-promoting effects. By enforcing stable cell-cycle arrest, TIS prevents proliferation of damaged cancer cells while simultaneously reprogramming the tumor microenvironment (TME) through the senescence-associated secretory phenotype (SASP). This secretome recruits and activates innate and adaptive immune effectors, thereby enhancing immune clearance and sensitizing tumors to immunotherapies such as immune checkpoint inhibitors. However, the chronic persistence of senescent cells and sustained SASP can paradoxically foster immune suppression, angiogenesis, epithelial–mesenchymal transition, and tumor relapse. Preclinical data demonstrate that combining senescence-inducing therapies with immunotherapies produces synergistic effects, particularly when paired with senolytic agents to eliminate residual senescent cells. Early clinical trials, especially those integrating CDK4/6 inhibitors with PD-1/PD-L1 blockade, highlight promising translational opportunities but also underscore critical challenges, including therapy sequencing, SASP heterogeneity, and T-cell suppression. Biomarker development, including advancements in senescence detection methods , remains essential to monitor senescence dynamics and immune modulation in real time. This review synthesizes mechanistic insights into TIS, its immunological interplay, and emerging therapeutic strategies, advocating for a rational “induce–prime–purge” framework. Leveraging TIS in combination with immunotherapies and senolytics holds the potential to transform refractory tumors into immune-responsive states while minimizing risks of relapse.

Main Body

Therapy-induced senescence (TIS) has emerged as a critical tumor-suppressive mechanism that contributes to the efficacy of many cancer therapies. Unlike apoptosis, senescence is a state of stable cell cycle arrest in which tumor cells remain metabolically active but cease to proliferate. TIS can be induced by a variety of treatments, including chemotherapy, radiation, and targeted agents such as alisertib , which induce non-lethal cellular stress or DNA damage [1, 2]. By halting tumor cell division, TIS provides a potent, though sometimes temporary, barrier to cancer progression [3]. Even in tumors with defective apoptotic pathways, senescence can serve as a fail-safe response to therapy, reinforcing its relevance across various cancer types [4]. Beyond its direct effect on tumor cell proliferation, TIS also exerts a profound influence on the tumor microenvironment (TME) through the senescence-associated secretory phenotype (SASP). SASP encompasses a diverse array of secreted factors, including pro-inflammatory cytokines, chemokines, growth factors, and proteases (Table 1). These molecules can recruit and activate various components of the immune system, including T cells, natural killer (NK) cells, macrophages, and dendritic cells (DCs), thereby facilitating immune-mediated clearance of senescent cells [5]. However, SASP can also have deleterious effects by promoting a pro-tumorigenic environment, angiogenesis, and immune suppression in some contexts [3, 6]. The dual nature of SASP underscores the need for precise modulation when exploiting TIS in cancer therapy. The aim of this review is to provide a comprehensive synthesis of TIS as both a tumor-suppressive mechanism and a therapeutic target in cancer. It examines the molecular pathways through which diverse anticancer treatments trigger senescence, the dual role of SASP in immune activation and suppression, and the capacity of TIS to remodel the TME. The review further highlights how senescence induction can synergize with immunotherapies, particularly immune checkpoint inhibitors (ICIs), while also considering the risks of chronic SASP and senescence escape. Finally, it evaluates emerging strategies such as senolytic agents, alongside the development of predictive biomarkers, to optimize TIS-based interventions.

Table 1. SASP molecules and their functions in cancer

Acronyms and Full Names:
CCL2 (MCP-1): Chemokine (C-C motif) ligand 2, also known as Monocyte Chemoattractant Protein-1
CCL5 (RANTES): Chemokine (C-C motif) ligand 5, also known as Regulated on Activation, Normal T Cell Expressed and Secreted
CXCL1 / CXCL2: Chemokine (C-X-C motif) ligand 1 / 2
CXCL8 (IL-8): Chemokine (C-X-C motif) ligand 8, also known as Interleukin 8
CXCL9: Chemokine (C-X-C motif) ligand 9
CXCL10: Chemokine (C-X-C motif) ligand 10
DAMP: Damage-associated Molecular Pattern
GM-CSF: Granulocyte-Macrophage Colony-Stimulating Factor
HMGB1: High-Mobility Group Box 1
IGFBP-3 / IGFBP-7: Insulin-like Growth Factor Binding Protein 3 / 7
IL-6: Interleukin 6
IL-1α: Interleukin 1 alpha
IL-1β: Interleukin 1 beta
IL-10: Interleukin 10
MMP1 / MMP3 / MMP9: Matrix Metalloproteinase 1 / 3 / 9
PD-L1: Programmed Death-Ligand 1
PGE2: Prostaglandin E2
TGF-β: Transforming Growth Factor beta
TNF-α: Tumor Necrosis Factor alpha
VEGF: Vascular Endothelial Growth Factor

TIS triggered by genotoxic stress represents a well-characterized mechanism by which cancer cells undergo irreversible growth arrest in response to DNA-damaging agents .