Senescent cancer-associated fibroblasts in cancer progression: From formation to therapeutic opportunities

Cancer-associated fibroblasts (CAFs) are a key cellular component of the tumor microenvironment (TME), which comprises distinct subtypes, each exhibiting unique and significant roles in cancer development. Senescent cancer-associated fibroblasts (senCAFs) are a newly identified subset of CAFs characterized by high expression of senescence-associated markers. Notably, senCAFs significantly promote tumor malignancy through the secretion of diverse senescence-associated secretory phenotype (SASP) factors, such as interleukin-6 (IL-6), interleukin-8 (IL-8), matrix metalloproteinases (MMPs), and transforming growth factor-β (TGF-β), thereby facilitating tumor cell proliferation, invasion, angiogenesis, immunosuppression, and resistance to cancer therapy. Consequently, targeting senCAFs-either through selective clearance of this cell subset or suppression of their SASP-represents a promising approach for cancer treatment. Emerging therapies include pharmacological inhibition of key SASP regulatory pathways (e.g., JAK/STAT3 and NF-κB) and antagonists targeting individual SASP components. Additionally, senolytic agents and therapies targeting senCAF-specific markers (e.g., TSPAN8) are being actively explored. Furthermore, immunotherapies, including CAR-T cells targeting senescence-associated surface proteins, provide intriguing avenues. These advances highlight senCAFs as attractive therapeutic targets and underscore the potential for integrating SASP inhibitors and senolytic agents into precision oncology paradigms.