Macrophages are highly adaptable immune cells that play critical roles in various biological processes, including immune responses, tissue maintenance, and the development of numerous diseases (Mehla & Singh, 2019). These cells can polarize into distinct phenotypes, most notably M1 (pro-inflammatory) and M2 (anti-inflammatory), which critically modulate immune reactions and maintain tissue balance (Cao et al., 2024). M1 macrophages, often referred to as classically activated macrophages, are typically triggered by pro-inflammatory agents such as lipopolysaccharides. These cells are characterized by a pronounced expression of major histocompatibility complex (MHC) class II molecules, including Human Leukocyte Antigen (HLA)-DR, inducible nitric oxide synthase (iNOS), CD68 and CD11c (Iizuka et al., 2025; Shapouri-Moghaddam et al., 2018). Their primary function involves combating pathogens and tumor cells, manifesting strong pro-inflammatory responses through the secretion of cytokines like TNF-α, IL-1β, and IL-6, along with the generation of reactive oxygen species (ROS) (Ishida et al., 2023; Shapouri-Moghaddam et al., 2018). In contrast, M2 macrophages, also known as alternatively activated macrophages, are stimulated by anti-inflammatory cytokines such as IL-4 and IL-13 (Mantovani et al., 2004). These macrophages demonstrate anti-inflammatory characteristics and facilitate tissue repair and remodeling by releasing anti-inflammatory cytokines, including IL-10 and TGF-β (Mai et al., 2021). Research has identified several factors involved in regulating M1/M2 polarization, including the IL-13/IL-4Rα signaling pathway, IL-33, Notch signaling (Liu et al., 2025; Mai et al., 2021). Moreover, metabolic reprogramming is crucial for macrophage polarization. Typically, M1 macrophages mainly depend on aerobic glycolysis, while M2 macrophages primarily rely on oxidative metabolism (Li et al., 2023; Raines et al., 2022). Fatty acid oxidation (FAO) significantly contributes to M2-like polarization by promoting the metabolic adaptations that underpin the tumor-promoting function of these macrophages (Jha et al., 2015; Vitale, Manic, Coussens, Kroemer, & Galluzzi, 2019). In addition, amino acid metabolism, particularly glutamine metabolism, has been proven to be of great importance in the polarization and function of tumor-associated macrophages (TAMs) (Liu et al., 2023; Wang, Zhang, Xue, Neculai, & Zhang, 2024). Lactic acid also influences macrophage polarization by signaling to TAMs via G-protein-coupled receptor 132 (GPR132), inducing their polarization to an immunosuppressive “M2-like” phenotype (Chen et al., 2017; De Martino, Rathmell, Galluzzi, & Vanpouille-Box, 2024; Shi, Yasui, & Hara-Chikuma, 2022; Xu, Liu, Li, & Geng, 2024).

Recent research has highlighted the shortcomings of the conventional binary classification system of M1 and M2, indicating that macrophages exist along a spectrum of activation states shaped by their surrounding microenvironment (Ishida et al., 2023). Among the essential functions of macrophages are the elimination of pathogens and cellular debris, the production of pro-inflammatory cytokines, and the coordination of tissue repair mechanisms, all crucial for sustaining homeostasis and responding to pathological challenges such as cancer and chronic inflammation (Liu et al., 2022). Beyond their contributions to innate immunity, macrophages significantly modulate adaptive immunity via antigen presentation and cytokines to T cells and by releasing signals that guide T cell differentiation (Italiani & Boraschi, 2014; Muntjewerff, Meesters, & Bogaart, 2020). The inherent dual functionality of macrophages highlights their crucial role in both protective immunity and disease progression, particularly in cancer, where their effects can either inhibit or promote tumor growth based on their polarization status (Fig. 1) (Liu et al., 2022; Vemuri et al., 2023).

Cellular aging, commonly referred to as senescence, represents a fundamental biological process whereby cells gradually lose their capacity to divide and perform their functions effectively. This phenomenon is triggered by various stressors such as DNA damage, oxidative stress, and telomere attrition, ultimately contributing to the aging process and the emergence of age-related diseases, including cancer (Antonangeli, Zingoni, Soriani, & Santoni, 2019; Niklander, Aránguiz, Faunes, & Martínez-Flores, 2023; Yamauchi & Takahashi, 2024). Senescent cells exhibit characteristic phenotypic alterations, encompassing changes in morphology and the release of pro-inflammatory mediators, collectively referred to as the senescence-associated secretory phenotype (SASP), which comprises chemokines (e.g., CXCR2), inflammatory cytokines (IL-6 and IL-8), as well as growth factors and matrix metalloproteinases (MMPs), all of which modify the tissue microenvironment and influence tumorigenesis (Ghosh & Capell, 2016; Ohtani, 2022; Wang & Dreesen, 2018; Yang, Liu, Hong, Zeng, & Zhang, 2021). The interplay between cellular aging and cancer is intricate and often contradictory (Nardella, Clohessy, Alimonti, & Pandolfi, 2011). Research indicates that senescent cells may inhibit the proliferation of potential cancer cells, thereby acting as a protective barrier against tumorigenesis (Dou & Berger, 2018; Milanovic et al., 2018; Yang et al., 2021). However, an increasing body of evidence suggests that these senescent cells can foster tumor progression and enhance malignancy under certain circumstances (Wang, Kohli, & Demaria, 2020). By promoting inflammation, a phenomenon frequently referred to as “inflamm-aging”, senescent cells can create a tumor-promoting environment, altering extracellular matrix composition and affecting the behavior of adjacent cells, thus perpetuating the cycle of senescence and facilitating tumor development (Birch & Gil, 2020; D'Arino et al., 2023). Besides, the expression of CD73 by macrophages, induced through cellular senescence, serves as a pivotal metabolic immune checkpoint within the senescent tumor microenvironment (Deng et al., 2024). This dual functionality of senescence underscores its critical role in cancer biology (Fig. 2), with recent investigations proposing that targeting senescent cells or modulating the SASP could present innovative therapeutic strategies for cancer management (Ma et al., 2020; Takasugi, Yoshida, & Ohtani, 2022).

The investigation into the interplay between macrophages and cellular senescence is crucial for understanding the underlying mechanisms of cancer and for identifying potential therapeutic strategies. Macrophages play a pivotal role in the process of cellular senescence and the associated SASP. They significantly influence immune responses and contribute to the development of various age-related ailments, including chronic inflammation, cardiovascular diseases, and neurodegenerative disorders (Behmoaras & Gil, 2021; Nie, Zhang, Wang, Zhou, & Wang, 2019). Moreover, the interaction between macrophages and senescence is reciprocal. Senescent macrophages can exacerbate inflammation and tissue injury, leading to age-related conditions such as atherosclerosis, Alzheimer's disease, and osteoarthritis (Cheng et al., 2024; Fülöp, Dupuis, Witkowski, & Larbi, 2016; Vellasamy et al., 2022; Wang et al., 2024). On the other hand, the ability of macrophages to eliminate senescent cells represents a crucial anti-cancer defense mechanism (Haston et al., 2023; Kang et al., 2011; Song, An, & Zou, 2020; Wang, Liu, Hu, Yang, & Qiu, 2025). As such, exploring the relationship between macrophages and senescence is vital not only for advancing our understanding of senescence and its health implications but also for developing innovative cancer therapies.

This review highlights the mechanisms by which macrophages identify and phagocytose senescent cells, underscoring their critical role in maintaining tissue homeostasis. We also examine the ramifications of macrophage dysfunction on cellular senescence, assessing the potential impacts of targeting senescent cells and macrophages in cancer treatment. Through a comprehensive analysis of these interactions, this paper seeks to clarify the significance of macrophages and cellular senescence in tumorigenesis, providing valuable insights for cancer therapy.