Senescence-associated transcriptional reprogramming in the tumor immune microenvironment: Mechanistic layers and therapeutic opportunities

Xiao Yu; Jianlei Xing; Xudong Zhao; Qiang Shan

doi:10.70401/acrt.2026.0040

Senescence-associated transcriptional reprogramming in the tumor immune microenvironment: Mechanistic layers and therapeutic opportunities

Xiao Yu

Jianlei Xing

Xudong Zhao

1,*

Qiang Shan

2,*

Affiliation +

*Correspondence to: Xudong Zhao, Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning, China. E-mail: donold@126.com
Qiang Shan, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences, Suzhou 215123, Jiangsu, China. E-mail: sq@ism.pumc.edu.cn

Ageing Cancer Res Treat. 2027;4:202626. 10.70401/acrt.2026.0040

Received: June 01, 2026Accepted: September 15, 2026Published: September 15, 2026

This article belongs to the Special lssue Immunosenescence and Cancer: From Mechanisms to Therapy

This manuscript is made available in its unedited form to allow early access to the reported findings. Further editing will be completed before final publication. As such, the content may include errors, and standard legal disclaimers are applicable.

Abstract

The tumor immune microenvironment (TIME) is a principal determinant of tumor progression, metastatic dissemination, and therapeutic response. Cellular senescence, primarily through the senescence-associated secretory phenotype (SASP), progressively reshapes the TIME toward immunosuppressive and therapy-resistant states. Here, we propose an integrative framework of “senescence-associated transcriptional reprogramming” comprising three mechanistic layers: endogenous inflammation-driven signaling centered on the cGAS-STING-NF-κB-IFN hub; lineage-specific epigenetic lock-in in immune cells; and metabolic-epigenetic coupling. We further discuss mechanism-guided, temporally optimized senolytic and senomorphic strategies, particularly relevant to elderly cancer patients, to rationally reverse senescence-driven tumor immune tolerance and enhance current immunotherapies.

Keywords

Tumor immune microenvironment, cellular senescence, senescence-associated secretory phenotype, senescence-associated transcriptional reprogramming, senolytics/senomorphics

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Yu X, Xing J, Zhao X, Shan Q. Senescence-associated transcriptional reprogramming in the tumor immune microenvironment: Mechanistic layers and therapeutic opportunities. Ageing Cancer Res Treat. 2027;4:202626. https://doi.org/10.70401/acrt.2026.0040