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Review
. 2023 Nov 14:14:1295684.
doi: 10.3389/fimmu.2023.1295684. eCollection 2023.

Unraveling the enigma of tumor-associated macrophages: challenges, innovations, and the path to therapeutic breakthroughs

Shengwen Shao #  1 , Huilai Miao #  2   3 , Wenxue Ma  4
Affiliations
Review

Unraveling the enigma of tumor-associated macrophages: challenges, innovations, and the path to therapeutic breakthroughs

Shengwen Shao et al. Front Immunol. .

Abstract

Tumor-associated macrophages (TAMs) are integral to the tumor microenvironment (TME), influencing cancer progression significantly. Attracted by cancer cell signals, TAMs exhibit unparalleled adaptability, aligning with the dynamic tumor milieu. Their roles span from promoting tumor growth and angiogenesis to modulating metastasis. While substantial research has explored the fundamentals of TAMs, comprehending their adaptive behavior, and leveraging it for novel treatments remains challenging. This review delves into TAM polarization, metabolic shifts, and the complex orchestration of cytokines and chemokines determining their functions. We highlight the complexities of TAM-targeted research focusing on their adaptability and potential variability in therapeutic outcomes. Moreover, we discuss the synergy of integrating TAM-focused strategies with established cancer treatments, such as chemotherapy, and immunotherapy. Emphasis is laid on pioneering methods like TAM reprogramming for cancer immunotherapy and the adoption of single-cell technologies for precision intervention. This synthesis seeks to shed light on TAMs' multifaceted roles in cancer, pinpointing prospective pathways for transformative research and enhancing therapeutic modalities in oncology.

Keywords: cancer immunotherapy; clinical trials; phenotypic diversity; regulatory signaling pathways; tumor microenvironment (TME); tumor-associated macrophages (TAM).

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

Figure 1
Figure 1
Dynamics of TAM polarization within the TME. TAMs, originating from circulating monocytes, differentiate into macrophages within the TME in response to specific signals. Key influencers include the cytokine IFN-γ, sourced from activated CD8+ T cells and NK cells, as well as a combination of IFN-γ, IL-2, IL-10, and TNF-α/β from Th1 cells (CD4+ T cells). External factors like LPS, predominantly derived from Gram-negative bacteria within the tumor microenvironment, and other TLR agonists, which are typically released from bacteria, and necrotic tumor cells, or systemic sources, favor the development of the M1 macrophage phenotype. In contrast, potent Th2 cytokines, such as IL-4 and IL-13, along with hypoxic conditions, steer macrophages toward the TAM2 direction. TAM1 macrophages, influenced dominantly by IFN-γ and LPS, assume a pro-inflammatory stance, producing cytokines like IL-1β, IL-6, and TNF-α that can promote tumor cell apoptosis. On the other hand, TAM2 macrophages, shaped by IL-4 and IL-13, exhibit an anti-inflammatory profile, secreting cytokines such as IL-10 and TGF-β, which not only suppress immune responses but also enhance angiogenesis processes.
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The author(s) declare that no financial support was received for the research, authorship, and/or publication of this article.