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<p>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 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.</p>

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A narrative review of therapy-induced senescence in cancer: mechanisms, immune interplay, and therapeutic opportunities

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年12月8日

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  • Henry Sutanto,
  • Alfan Ahkami,
  • Deasy Fetarayani,
  • Pradana Zaky Romadhon

摘要

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 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.