Therapeutic targeting of tumour-associated macrophage receptors

Abstract

Tumour-associated macrophages (TAM) are present in the majority of tumours, where they comprise one of the most abundant cell types, influencing tumour progression, metastasis, therapy resistance, and relapse. Hence, there is a great interest in targeting TAMs to improve and complement anti-cancer treatments. However, further studies are needed to validate the potential of exploiting TAM cell surface markers for cancer immunotherapy. Here, we review the function of TAMs, their involvement in tumorigenesis, metastasis, and therapy resistance. Furthermore, we summarize the current landscape of key TAM cell surface receptors that are being investigated as potential targets for cancer immunotherapy, highlighting the promise and challenges associated with these approaches.

Keywords: immunotherapy; monoclonal antibodies; tumour microenvironment; tumour-associated macrophages.

Figure 1.

Macrophage polarization is dependent on different environmental cues. Stimuli within the microenvironment allows for differentiation of monocytes into different macrophage states with a particular array of functions. Although macrophages represent a continuum, they can be broadly divided into “M1-like” and “M2-like”, with the latter being further subdivided into M2a, M2b, M2c, and M2d phenotypes. All of these subsets express different cytokines, chemokines, and receptors allowing them to perform different functions. Created in BioRender. Martins, R. (2025) https://biorender.com/v67o359

Figure 2.

Anti-tumorigenic and pro-tumorigenic functions of TAMs. Tumour-educated macrophages can promote (right) or suppress (left) tumour development, depending on their activation status and environmental cues. Anti-tumour macrophages can induce cancer cell death via secretion of mediators or through direct cellular interactions. On the other hand, pro- tumour TAMs can mediate immunosuppression by secreting factors into the TME and expressing surface molecules that lead to recruitment of Tregs and inhibition of CTLs. In addition, TAMs have been linked to increased invasion and metastasis, angiogenesis/lymphoangiogensis, and resistance to radiotherapy and chemotherapeutics, as well as disease recurrence. Created in BioRender. Martins, R. (2025) https://biorender.com/s36p829

Figure 3.

Current therapeutic strategies targeting TAM cell surface receptors. The main therapeutic strategies targeting TAM receptors include increasing phagocytic ability (impairing “don’t eat me” signal pathways), repolarization (from pro- to anti-tumour), reducing and decreasing survival and relocation, and immune checkpoint blockade with antibodies to relieve immunosuppression. The process of macrophage-mediated ADCP involves the recognition of tumour cells by therapeutic antibodies, such as rituximab (anti-CD20) and trastuzumab (anti- HER2) which then engage FcγRs on macrophages. Antibodies targeting “don’t eat me” receptors on macrophages (e.g., SIRPα and Siglec-10) or target cells can enhance ADCP and improve immunotherapy responses. Created in BioRender. Martins, R. (2025) https://biorender.com/h79n993

Figure 4.

Inhibitory leukocyte immunoglobulin-like receptors. LILRs consist of 5 membrane-bound and one soluble LILRB. Of these receptors, LILRB1, LILRB2, LILRB3 and LILRB5 each contain 4 Ig-like extracellular domains, while LILRB4 contains 2 extracellular Ig-like domains. While LILRB1-5 contains 4, 3, 4, 3 and 2 ITIM domains intracellularly, respectively, LILRB2S is not membrane bound and lacks intracellular ITIMs. Created in BioRender. Martins, R. (2025) https://biorender.com/a18o606