Macrophages in Cancer: Immunosuppression, Immunoregulation, and Immunotherapy

Dear Colleagues,

Macrophages are innate immune cells known for their role in phagocytosis, antigen presentation, and cytokine production. They exhibit remarkable plasticity, adapting to various microenvironmental signals that confer a spectrum of functional states, ranging from pro-inflammatory (M1) to anti-inflammatory or pro-tumorigenic (M2) phenotypes. Within the tumor microenvironment, macrophages are predominantly polarized toward an M2-like state, contributing to tumor growth, metastasis, and immunosuppression. Their dynamic functions in cancer immunosuppression and immunoregulation and as targets for immunotherapy are the focus of current research efforts.

Tumor-associated macrophages (TAMs) often exhibit an M2 phenotype, which supports cancer progression through various mechanisms. They produce immunosuppressive cytokines like IL-10 and TGF-β, dampening the cytotoxic functions of T cells and natural killer (NK) cells. Furthermore, they release enzymes such as arginase that deplete metabolites necessary for immune cell function and express checkpoint molecules like PD-L1, contributing to immune evasion by the tumor. Additionally, they promote angiogenesis and remodel the extracellular matrix, facilitating tumor dissemination.

While TAMs tend to support the development of cancer, M1-like macrophages harbor tumoricidal activity. The immunoregulatory role of macrophages depends on a balance between these opposing phenotypes. M1 macrophages release pro-inflammatory cytokines and reactive oxygen species, which can destroy tumor cells. They also present antigens to T cells, initiating adaptive immune responses. The plastic nature of macrophages allows them to adapt to signals from other immune cells, chemokines, and therapeutic agents, potentially reversing immunosuppression and restoring anti-tumor immunity.

Macrophages are emerging as pivotal targets and effectors in cancer immunotherapy. Strategies to modulate macrophage function include blocking their recruitment to the tumor site, inhibiting M2 polarization, and enhancing their phagocytic and antigen-presenting capacities. Clinical trials are ongoing for agents repolarizing TAMs toward an M1-like phenotype or targeting their immunosuppressive functions. Additionally, macrophages engineered to express chimeric antigen receptors (CARs) may provide a new avenue for cellular therapies in cancer.

Dr. Abdullah Saeed
Guest Editor

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• macrophage
• immunosuppression
• immunoregulation
• immunotherapy
• tumor immune microenvironment