**Background:** Metastasis is the most lethal consequence of cancers, requiring cancer cells to leave the primary site, disseminate through the bloodstream, and colonize secondary organs. Cellular senescence—a stable cell cycle arrest state driven by stress responses—has traditionally been viewed as tumor-suppressive in the short term. However, emerging evidence indicates that senescent cells, through their senescence-associated secretory phenotype (SASP) and other features, can paradoxically promote cancer progression and metastasis. This review synthesizes current knowledge on how senescent cells contribute to each step of the metastatic cascade.
**Methods:** This is a narrative review that synthesizes published literature on cellular senescence and metastasis. The authors examine evidence from in vitro studies, animal models, and human clinical specimens across multiple cancer types. They organize the discussion around key metastatic processes: invasion, colonization, metabolic adaptation, and immune modulation. The review draws parallels between placental development (a physiologically invasive process) and cancer metastasis, and discusses shared mechanisms including cell fusion, polyploidy, epithelial-to-mesenchymal transition (EMT), angiogenesis, extracellular matrix (ECM) remodeling, immune suppression, and anoikis resistance.
**Key Results:** The authors present several lines of evidence linking senescence to metastasis: (1) Senescent cells are detected in lymph nodes and lymphovascular channels in human thyroid cancer, and accumulate at marginal zones of primary tumors. (2) In melanoma, soluble E-cadherin produced by senescent cells promotes ECM remodeling and increases invasion; elimination of senescent cells suppressed lung metastasis. (3) Polyploid Giant Cancer Cells (PGCCs), which exhibit therapy-induced senescence markers, have been identified in multiple cancers including colon, melanoma, lung, pancreas, breast, ovarian, prostate, renal, thyroid and urinary bladder. Whole-Genome Doubling was identified in 37% of solid tumors and proposed as a marker of poor prognosis. (4) Senescent fibroblasts and their conditioned medium stimulate premalignant epithelial cells to proliferate and form tumors in mice, largely through IL-6 and IL-8. (5) Cancer-associated fibroblasts (CAFs) frequently exhibit SASP-like factors; TGF-β from colorectal cancer cells stimulates CAFs to secrete IL-11, activating STAT3 signaling and favoring metastatic cell survival in the liver. (6) Senescent cells upregulate anti-apoptotic proteins BCL-W and BCL-XL; pharmacological inhibition of these selectively induces apoptosis in senescent cells. (7) Senescent thyrocytes confer anoikis resistance to co-cultured thyroid cancer cells via CXCR4-CXCL12 signaling. (8) Metabolically, senescent cells show increased glycolysis, NAD+ accumulation via NAMPT upregulation, and elevated fatty acid synthesis via FASN—all pathways also implicated in metastasis. CD36, a fatty acid transporter linked to metastasis-initiating cells, is rapidly upregulated in senescent cells.
**Clinical Implications:** The authors propose two therapeutic strategies: (1) inhibiting the SASP using drugs like rapamycin or metformin, which have shown potential to prevent cancer progression; and (2) eliminating senescent cells using senolytics. A 'one-two-punch' approach—first inducing senescence with chemotherapeutics, PARP inhibitors, or CDC7 inhibitors, then eliminating these cells with senolytics—may improve treatment outcomes. More targeted approaches include senolytic CAR T cell therapy (e.g., uPAR-specific CAR T cells, which effectively eliminated senescent cells in a lung cancer mouse model) and antibody–drug conjugates targeting senescence-specific surface antigens. The authors emphasize that the context-dependency of senescence effects (beneficial vs. deleterious) remains a major challenge, and that dissecting senescence heterogeneity in human cancers is essential for developing precise interventions.