Beyond polarization: macrophage senescence in immunoregulation and cancer therapy

Abstract

Cancer incidence is increasing globally, presenting significant health challenges due to its severe impact on morbidity and mortality. As a disease closely linked to aging, the prevalence of cancer is expected to increase with increasing age, underscoring the need for comprehensive research into its mechanisms and treatments. Macrophages, which are central to the immune system, play a paradoxical dual role in cancer progression. While they can suppress tumor growth, tumor-associated macrophages (TAMs) frequently facilitate tumor development and metastasis, a complexity that is further intricate by the aging process. As macrophages transition into senescent cells, they undergo changes, including shifts in cytokine profiles, reduced phagocytic activity, and altered metabolism. These senescent macrophages contribute to cancer progression by creating an immunosuppressive environment, promoting angiogenesis, and supporting tumor invasion. This review explores the intricate functions of senescent macrophages in cancer, highlighting their implications for tumor biology and their potential as therapeutic targets. We discuss strategies to manipulate senescent macrophages to enhance current cancer therapies, emphasizing the importance of understanding their mechanisms to advance cancer treatment.

Keywords: age-related diseases; cancer microenvironment; macrophage senescence; senescence-associated secretory phenotype (SASP); therapeutic targeting.

Figure 1

Functional and cellular changes in senescent macrophages. Macrophage senescence is a state of permanent cell cycle arrest characterized by increased activity of senescence-associated beta-galactosidase (SA-β-gal); the overexpression of senescence biomarkers such as p16INK4a, p21CIP1, p53, CD38, and CX3CR1; and the secretion of senescence-associated secretory phenotype (SASP) factors, including IL-1, IL-6, IL-8, and matrix metalloproteinases (MMPs). These changes are associated with morphological alterations such as increased cell size and nuclear deformities, metabolic reprogramming leading to altered energy production, compromised polarization capacity resulting in an inability to effectively switch between the M1 and M2 phenotypes, and impaired phagocytic function with a reduced capacity to engulf pathogens and cellular debris.

Figure 2

Mechanisms of macrophage senescence in cancer. Macrophage senescence involves a complex interplay of various mechanisms, including genomic instability leading to DNA damage response activation, oncogene mutations that trigger cell cycle arrest, telomere attrition causing replicative senescence, mitochondrial dysfunction resulting in increased reactive oxygen species (ROS) production, metabolic reprogramming shifting toward glycolysis, altered intracellular communication with disrupted signaling pathways, chronic inflammation induced by persistent SASP factor secretion, and defective type 2 immune signaling characterized by impaired anti-inflammatory responses. These mechanisms collectively contribute to the development and progression of cancer by creating an immunosuppressive TME and promoting tumor cell survival and proliferation.

Figure 3

Impact of macrophage senescence in the TME. Senescent macrophages significantly influence the tumor microenvironment (TME) through multiple pathways. They release an array of proinflammatory cytokines, such as IL-6 and TNF-α, which promote tumor cell proliferation and survival. By modulating immune cell interactions, senescent macrophages can attract regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), thereby establishing an immunosuppressive milieu that hinders antitumor immune responses. Additionally, they contribute to angiogenesis by secreting vascular endothelial growth factor (VEGF), increase extracellular matrix (ECM) stiffness through the action of matrix metalloproteinases (MMPs), and facilitate immune evasion by downregulating major histocompatibility complex (MHC) molecules on tumor cells, making them less recognizable to the immune system.

Figure 4

Macrophage senescence-targeted therapeutic strategies in cancers. Macrophage senescence-targeted therapy encompasses a diverse range of approaches aimed at reversing senescence and eliminating senescent macrophages. These include senolytic drugs designed to selectively induce apoptosis in senescent cells, such as navitoclax and the dasatinib/quercetin combination, which have shown promise in preclinical models by reducing tumor burden and enhancing treatment efficacy. CAR-M therapy represents an innovative strategy in which macrophages are engineered to express chimeric antigen receptors (CARs) that specifically target senescent cells within the TME.