Effects of senescent macrophages on tumors. (IMAGE)

China Anti-Cancer Association

Effects of senescent macrophages on tumors.

Caption

Effects of senescent macrophages on tumors. (A) Inflammation: senescent macrophages secrete factors, such as IL-6, IL-8, and IL-1α, that form the SASP, which establishes an immunosuppressive environment. SASP factors activate NF-κB, thus promoting MDSC and Treg infiltration, suppressing T and B cell functions, and advancing tumor progression. (B) Polarization: aging macrophages often polarize to the M2 phenotype, which promotes tumor progression through expression of IL-10, Arg1, and CD163, thereby enhancing angiogenesis and immune evasion. (C) Metabolic changes: aging macrophages show diminished NAD+ levels, impaired phagocytosis, and mitochondrial dysfunction. Lactate accumulation maintains the M2 phenotype and promotes tumor survival, whereas mitochondrial damage and oxidative stress worsen inflammation via NLRP3 activation. (D) Infiltration: increased CCR2 expression in senescent macrophages enhances their response to tumor-secreted chemokines (CCL2 and VEGF) and leads to stronger infiltration and tumor progression. (E) Phagocytosis: senescent macrophages show impaired phagocytosis because of IL-10 secretion by peritoneal B cells and decreased scavenger receptor expression, such as Mrc1, thus weakening tumor-clearing ability. Additionally, dysregulation of circadian genes, such as Klf4, worsens functional decline, impairs tumor suppression, and promotes tumor development, thus affecting treatment outcomes. SASP, senescence-associated secretory phenotype; IL, interleukin; MMPs, matrix metalloproteinases; MDSCs, myeloid-derived suppressor cells; EMT, epithelial-mesenchymal transition; NAD, nicotinamide adenine dinucleotide; ROS, reactive oxygen species; NLRP3, NOD−, LRR− and pyrin domain-containing protein 3; VEGF, vascular endothelial growth factor; CCL2, C-C motif chemokine ligand 2; CCR2, C-C motif chemokine receptor 2.

Credit

Cancer Biology & Medicine

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