Immunoregulatory mechanisms in the aging microenvironment: Targeting the senescence-associated secretory phenotype for cancer immunotherapy.
10.1016/j.apsb.2025.07.022
- Author:
Haojun WANG
1
;
Yang YU
2
;
Runze LI
3
;
Huiru ZHANG
1
;
Zhe-Sheng CHEN
4
;
Changgang SUN
5
;
Jing ZHUANG
5
Author Information
1. College of First Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250011, China.
2. State Key Laboratory of Quality Research in Chinese Medicine, Faculty of Chinese Medicine, Macau University of Science and Technology, Macau SAR 999078, China.
3. State Key Laboratory of Traditional Chinese Medicine Syndrome, the Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou 510000, China.
4. Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA.
5. College of Traditional Chinese Medicine, Shandong Second Medical University, Weifang 261000, China.
- Publication Type:Review
- Keywords:
Aging;
Anti-tumor immunotherapy;
Immunoregulatory mechanisms;
Immunosenescence;
Immunotherapy;
PD-L1;
Senescence-associated secretory phenotype;
Tumor microenvironment
- From:
Acta Pharmaceutica Sinica B
2025;15(9):4476-4496
- CountryChina
- Language:English
-
Abstract:
The aging microenvironment, as a key driver of tumorigenesis and progression, plays a critical role in tumor immune regulation through one of its core features-the senescence-associated secretory phenotype (SASP). SASP consists of a variety of interleukins, chemokines, proteases, and growth factors. It initially induces surrounding cells to enter a state of senescence through paracrine mechanisms, thereby creating a sustained inflammatory stimulus and signal amplification effect within the tissue microenvironment. Furthermore, these secreted factors activate key signaling pathways such as NF-κB, cGAS-STING, and mTOR, which regulate the expression of immune-related molecules (such as PD-L1) and promote the recruitment of immunosuppressive cells, including regulatory T cells and myeloid-derived suppressor cells. This process ultimately contributes to the formation of an immunosuppressive tumor microenvironment. Furthermore, the article explores potential anti-tumor immunotherapy strategies targeting SASP and its associated molecular mechanisms, including approaches to inhibit SASP secretion or eliminate senescent cells. Although these strategies have shown promise in certain tumor models, the high heterogeneity among tumor types may result in varied responses to SASP-targeted therapies. This highlights the need for further research into adaptive stratification and personalized treatment approaches. Targeting immune regulatory mechanisms in the aging microenvironment-particularly SASP-holds great potential for advancing future anti-tumor therapies.
