A Review of Senescence-Associated Secretory Phenotype-Mediated Remodeling of the Tumor Microenvironment: Implications for Cancer Progression and Therapy.

BACKGROUND

Cellular senescence influences cancer progression through irreversible cell-cycle arrest, immune surveillance, and paracrine signaling mediated by the senescence-associated secretory phenotype (SASP). SASP comprises inflammatory cytokines, chemokines, growth factors, and matrix-remodeling enzymes that regulate the tumor microenvironment (TME).

OBJECTIVE

This review describes the current evidence on the mechanisms of SASP induction, its condition-dependent roles in cancer, TME remodeling, and emerging strategies targeting senescent cells and SASP signaling.

METHODS

Relevant literature was identified through searches on PubMed, Scopus, Web of Science, and Google Scholar using keywords related to cellular senescence, SASP, cancer, TME, senolytics, and senomorphics. Peer-reviewed English-language studies published primarily between January 2000- March 2026 were considered, including preclinical (in vitro, in vivo), and clinical studies investigating SASP induction and regulation, its role in cancer progression and TME remodeling, and therapeutic strategies targeting senescent cells or SASP signaling.

INTERPRETATION OF THE RETRIEVED ARTICLES: SASP exhibits both tumor-suppressive and tumor-promoting activities depending on cellular and tissue condition. While transient SASP may enhance antitumor immunity and suppress early tumorigenesis, persistent SASP, particularly during therapy-induced senescence (TIS), can promote tumor growth, angiogenesis, immune evasion, cancer stemness, metastasis, and therapeutic resistance. Senolytics and senomorphics have therefore emerged as promising approaches for targeting senescent cells and their detrimental secretory effects. SASP-associated molecules also show potential as biomarkers, although specificity and tissue-dependent heterogeneity remain major challenges.

CONCLUSION

Current evidence supports SASP as a major regulator of the TME and an important determinant of cancer progression and therapeutic response. Understanding the condition-dependent functions of SASP is critical for developing effective senescence-targeted cancer therapies.