Senescent macrophages in cancer: roles in tumor progression and treatment opportunities

Abstract

Senescent macrophages have emerged as dynamic cells within the tumor microenvironment that significantly promote tumor progression through complex cellular and molecular functional alterations. This review explores the multifaceted roles of macrophage senescence in cancer, and establishes links between senescent macrophages and tumor progression from multiple perspectives, on the basis of the first comprehensive analysis of the molecular mechanisms and pathways involved. By systematically examining the diverse changes in senescent macrophages, this review integrates and analyzes their effects on tumors, thus offering a comprehensive and novel theoretical foundation, and practical insights for cancer treatment. Notably, by integrating current molecular research and therapeutic advancements, we summarize novel therapeutic strategies targeting senescent macrophages, including senolytics, senescence modulators, and cutting-edge immunotherapies, thereby highlighting the potential of senescent macrophages as a therapeutic target and introducing new opportunities for cancer treatment.

Keywords: Macrophages; cancer; immunology; senescence; senotherapeutics.

Figure 1

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.

Figure 2

Three therapeutic strategies targeting senescent macrophages: senolytics, senomorphics, and senoreverters. Senolytics selectively induce apoptosis in senescent cells by inhibiting key anti-apoptotic pathways, including the BCL-2 family, PI3K/AKT, and insulin/IGF-1 signaling, thereby leading to cell death. Senomorphics, in contrast, suppress the pro-inflammatory and pro-tumorigenic effects of the SASP by inhibiting pathways such as NF-κB, JAK-STAT, and mTOR, thereby effectively blocking secretion without eliminating the cells. Finally, senoreverters reverse the senescent phenotype by targeting senescence biomarkers and key regulators, such as mTOR and NF-κB, thereby restoring cells to a pre-senescent state. BCL-2, B cell CLL/lymphoma-2; PI3K/AKT, phosphatidylinositol 3-kinase/protein kinase b; IGF-1, insulin-like growth factor 1; SASP, senescence-associated secretory phenotype; NF-κB, nuclear factor kappa-light-chain-enhancer of activated b cells; JAK-STAT, Janus kinase-signal transducer and activator of transcription; mTOR, mechanistic target of rapamycin.