Fig. 4

Components and potential effects of senescent cell in tumor. NF-κB signaling is activated in senescent cancer cells and elevates multiple production of IL-1α, IL-6, IL-8, CCL5, and growth factors like VEGF, FGF, PDGF, HMGB1, and MMP. To be detailed, IL-6, IL-8, CCL5, CXCL1, etc., help to recruit MDSCs to the TME to mediate protumorigenic effect of senescent cells, which block IL-1α signaling and antagonize the establishment of senescence in cancer cells. Simultaneously, MDSCs block immune surveillance by inhibiting CD8+ T cells and NK cells through IL-6 and CCL2, respectively, while IL-6 and IL-8 can recruit NK cells and T cells to reinforce immune surveillance. The ILs will spread senescence to surrounding cancer cells in a paracrine fashion, which further mediates tumor growth. The prominent SASP factors are involved in ECM processing and degradation, which can promote tumor cell proliferation and invasion. IL-6 secreted by senescent cancer cells or released from the ECM by MMPs recruits MDSCs, leading to an immunosuppressive TME. Moreover, the cleaved ECM components release growth factors such as VEGF, FGF, PDGF, and ILs that can promote tumor growth and EMT, promoting tumor metastasis. Additionally, MMPs also promote the release of many other cytokines and growth factors such as VEGF supporting tumorigenesis and chemokine CXCL1 to promote tumor growth. The SASP can stimulate blood vessel formation and vascular remodeling that contributes to tumor metastasis. Activated TLR4 promotes tumor progression in breast, prostate, and colon cancers and is associated with poor prognosis, but the antitumor activity is increased in skin cancers. TLR4 also recognizes HMGB1 and facilitates SASP phenotype formation. NF-κB, nuclear factor-κB; VEGF, vascular endothelial growth factor; FGF, fibroblast growth factor; PDGF, platelet-derived growth factor; MMP, matrix metalloproteinases; IL, interleukin; TME, tumor microenvironment; MDSCs, myeloid-derived suppressor cells; NK cell, natural killer cell; SASP, senescence-associated secretory phenotype; ECM, extracellular matrix