Targeting tumor-associated macrophages: Novel insights into immunotherapy of skin cancer

Abstract

Background: The incidence of skin cancer is currently increasing, and conventional treatment options inadequately address the demands of disease management. Fortunately, the recent rapid advancement of immunotherapy, particularly immune checkpoint inhibitors (ICIs), has ushered in a new era for numerous cancer patients. However, the efficacy of immunotherapy remains suboptimal due to the impact of the tumor microenvironment (TME). Tumor-associated macrophages (TAMs), a major component of the TME, play crucial roles in tumor invasion, metastasis, angiogenesis, and immune evasion, significantly impacting tumor development. Consequently, TAMs have gained considerable attention in recent years, and their roles have been extensively studied in various tumors. However, the specific roles of TAMs and their regulatory mechanisms in skin cancer remain unclear.

Aim of review: This paper aims to elucidate the origin and classification of TAMs, investigate the interactions between TAMs and various immune cells, comprehensively understand the precise mechanisms by which TAMs contribute to the pathogenesis of different types of skin cancer, and finally discuss current strategies for targeting TAMs in the treatment of skin cancer.

Key scientific concepts of overview: With a specific emphasis on the interrelationship between TAMs and skin cancer, this paper posits that therapeutic modalities centered on TAMs hold promise in augmenting and harmonizing with prevailing clinical interventions for skin cancer, thereby charting a novel trajectory for advancing the landscape of immunotherapeutic approaches for skin cancer.

Keywords: Immune checkpoint inhibitors; Immunotherapy; Skin cancer; Tumor-associated macrophages.

Graphical abstract

Fig. 1

Schematic representation illustrating the origin and categorization of TAMs. TAMs originate from three primary sources: tissue-resident macrophages, MDSCs, and monocytes. Upon stimulation by cytokines or chemokines, such as CSF-1, IL-34, CCL-2, etc., these cells undergo a transformation into TAMs. Subsequently, TAMs manifest diverse phenotypes influenced by polarisation, specifically differentiating into M1-like and M2-like macrophages, each assuming distinct roles. Moreover, M2-like macrophages can be further subdivided into four subtypes: M2a, M2b, M2c, and M2d.

Fig. 2

TAM engage in interactions with other immune cells in skin cancer. TAMs not only function as inhibitors for the cytotoxic effects of CD8⁺ T cells by expressing various immune checkpoint ligands in direct contact with them, but they also release a range of cytokines, particularly TGF-β and IL-10, which impact the functions of CD8⁺ T cells, NK cells, DCs, and Tregs. Additionally, TAMs collaborate with MDSCs and Tregs to exert immunosuppressive effects. Ultimately, TAMs play a central role in shaping an immunosuppressive TME that aids in the tumor's ability to evade the immune system.

Fig. 3

Role of TAMs in the immune microenvironment of skin cancer. TAMs play a pivotal role as a core cell population in the immune microenvironment of skin cancer. Immunosuppressive cell populations orchestrated by TAMs facilitate tumor progression while dampening the immune response. Conversely, an augmented presence of immune cells, such as cytotoxic T lymphocytes, is correlated with an improved clinical prognosis.

Fig. 4

Reprogramming TAMs enhances both adaptive and intrinsic immunity. Among the strategies for TAM reprogramming, five major approaches have emerged, including interfering with CSF-1/CSF-1R signalling, agonising CD40, inhibiting PI3Kγ, agonising TLR, and blocking CD47/SIRPα interaction. These approaches restore the original functions of macrophages, such as phagocytosis and antigen presentation, while also enhancing the tumor-killing capabilities of NK cells and CD8⁺ T cells, thereby achieving a dual antitumor effect through innate and adaptive immunity. Numerous small molecule drugs and biologics based on these therapeutic strategies are currently either available on the market or undergoing clinical trials, highlighting the prominent position of TAM reprogramming as a promising therapeutic approach.