A tumor is a battleground of cell behavior and cell signaling. All cells can influence the behavior of surrounding cells via the signals they produce, and the evolution of cancerous cells that exhibit unfettered replication and continual mutation might be thought of as a blind search for whatever will trigger surrounding cells into assisting with more rapid growth. One of the most effective outcomes for tumor cells is to produce signals that can suppress the anti-cancer activities of the immune system. This capability is near universal for solid tumors, as without the ability to co-opt immune cells the tumor would likely never have come into being in the first place.
The innate immune cells known as macrophages are important in normal tissue maintenance and regeneration, and are particularly important in both suppression and growth of cancers. So are cells that have become senescent, that cease to replicate and secrete signals to rouse the immune system to action. Macrophage presence and cellular senescence are initially protective against cancer: senescence of damaged cells draws the attention of macrophages and other immune cells to destroy those cells before they can become cancerous. Macrophages and senescent cells are later co-opted into supporting tumor growth, however, in much the same way in which they interact to promote regenerative growth following injury. In today’s open access paper, researchers discuss the overlap between these two considerations, the presence of senescent macrophages in tumor tissue. As they report, a great deal is known, but these are complex biochemistries, and much remains to be established.
Senescent macrophages in tumor: phenotypes, roles, and interventions
The tumor microenvironment (TME) refers to the local region in which tumor cells reside, incorporating a diverse array of non-tumor cell types, extracellular matrix (ECM) components, vascular networks, and soluble factors. This intricate milieu is critical in modulating tumor behavior and influencing therapeutic responses. TME-associated senescent cells manifest a dualistic role: on the one hand, senescence TME statue can inhibit tumor progression by slowing their proliferation; conversely, the dynamic interplay of immune cell functions and cytokines produced by senescent cells allows these senescence-associated factors to modify the immune escape mechanisms within the TME, thereby significantly promoting tumor growth and the spread of cancer to distant sites.
Macrophages are essential components of innate and adaptive immunity and are one of the major infiltrating immune cells in TME. These macrophages are known as tumor-associated macrophages (TAMs) and play a dual role in tumor initiation and progression, acting as promoters and tumorigenesis suppressors. Macrophages can be classified into two distinct subtypes, also known as the polarization states of macrophages: M1 type and M2 type. M1 macrophages are classically triggered, pro-inflammatory cells that exert direct tumor-suppressive effects by secreting pro-inflammatory cytokines, such as interleukin-6 (IL-6), and generating reactive oxygen species and reactive nitrogen species, all of which contribute to the amplification of anti-tumor immune responses. In contrast, M2 macrophages release immunosuppressive mediators, including IL-4, IL-10, and transforming growth factor-beta (TGF-β), which inhibit T cell and natural killer (NK) cell functionality, promote angiogenesis, and facilitate tumor cell invasion, thereby contributing to tumor progression.
Contrary to the disordered proliferation of tumor cells, immune cells such as macrophages present a state of exhaustion or senescence-related reprogramming in TME. As aging progresses, macrophages exhibit a progressive decline in phagocytic capacity, respiratory burst activity, levels of toll-like receptors (TLRs) and MHC class II (MHC-II), responsiveness to antigenic triggers, and the release of pro-inflammatory chemokines and cytokines, suggesting that the senescence of macrophages occurs with aging, and the molecular changes of senescent macrophages (sMACs) disrupt the regular immune cell dialog. In addition, in vivo animal experiments showed that elimination of sMACs could inhibit tumor growth, suggesting the clinical significance of combination therapy targeting sMACs. Nonetheless, there is still a lack of consensus regarding the characteristic phenotypes of sMACs within the TME and their mechanistic roles. This review aims to provide an overview of the current understanding of the tumor infiltration-sMACs, summarize the molecular characteristics and functional abnormalities of sMACs, and discuss the potential roles and interventions of sMACs.
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