The innate immune cells known as macrophages are found in tissues throughout the body, and their activities are important in tissue maintenance and regeneration. Macrophages can adopt different packages of behavior in response to circumstances. There are a number of ways to define these behaviors, but researchers usually refer to (a) M1 macrophages that are inflammatory and aggressive, focused on destroying pathogens and errant cells, versus (b) M2 macrophages that are anti-inflammatory and more focused on tissue maintenance. This split of activities becomes particularly important in aged, damaged, or cancerous tissue. Cancers are known to reprogram and subvert immune cells in order to fuel growth, and the macrophages present in cancerous tissue, known as tumor-associated macrophages, are front and center in that process.
In today's open access paper, the authors discuss how cellular senescence in tumor-associated macrophages is particularly important in determining how these macrophages accelerate tumor growth. One of the useful activities undertaken by senescent cells in normal tissue is to coordinate regeneration from injury, and the senescence-associated secretory phenotype (SASP) generated by senescent cells is as much pro-growth as it is pro-inflammatory. A tumor evolves to encourage macrophage senescence, which in turn supports unchecked replication of tumor cells.
The research community is very interested in the application of senotherapeutics to cancer. Indeed, many successful chemotherapeutic drugs of past years have turned out to be senotherapeutic in the light of more recent knowledge. That these drugs are capable of destroying senescent cells or changing their behavior explains their success. Separately, researchers are also very interested in manipulating tumor-associated macrophages to make tumors less aggressive, such as via attempts to force M2 macrophages in tumor tissue to adopt an M1 state, or otherwise stop supporting cancer growth in favor of attacking cancerous cells. These two areas of research interest dovetail well with one another.
Senescent macrophages in cancer: roles in tumor progression and treatment opportunities
Macrophages play critical roles in the tumor microenvironment (TME), where they influence tumor progression through their remarkable plasticity and environmental adaptability. Typically, pro-inflammatory M1 macrophages (classically activated macrophages) are found in healthy tissues; in contrast, the macrophages in the TME predominantly adopt a pro-tumorigenic M2 (alternatively activated macrophages) phenotype, which facilitates tumor progression via extracellular matrix remodeling, angiogenesis, and immune suppression. Consequently, tumor-associated macrophages (TAMs) are central to promoting tumor growth, invasion, and metastasis through paracrine signaling and other mechanisms.
The role of cellular senescence in tumor development, particularly the effects of senescent macrophages in the TME, has garnered increasing attention. Cellular senescence was initially considered a tumor-suppressive mechanism. However, senescence paradoxically promotes tumor progression, particularly via senescent macrophages. Senescent macrophages, after exposure to specific intrinsic and extrinsic stimuli, undergo cellular aging. These cells are typically characterized by upregulation of p16 Inhibitor of Cyclin-Dependent Kinase 4a (p16INK4a) and distinct features associated with the senescence-associated secretory phenotype (SASP). Through intrinsic senescence, therapeutic interventions, or external stimuli, senescent macrophages exhibit functional impairments including chronic inflammation, decreased antigen presentation, and impaired phagocytosis. These changes foster an immunosuppressive environment conducive to tumor growth.
Key in this process is the SASP, comprising cytokines, chemokines, proteases, and growth factors that disrupt the immune environment and enhance tumorigenesis. Notably, IL-6 is a prominent SASP factor contributing to a pro-inflammatory, tumor-promoting milieu. Emerging evidence highlighting that senescent macrophages exacerbate tumor progression through SASP secretion and immune dysregulation has underscored the importance of understanding their mechanisms. Therapeutic strategies targeting senescent macrophages, including senolytics, senomorphics, and senoreverters, as well as immunotherapies such as Chimeric Antigen Receptor T-cell (CAR-T) cells, offer promising avenues for halting tumor growth and reversing the harmful effects of the aging TME. Future research is expected to focus on optimizing these treatments and elucidating the interactions between senescent macrophages and tumor cells to improve clinical outcomes.
View the full article at FightAging
