Progress in tumor-associated macrophage (TAM)-targeted therapeutics

Abstract

As an essential innate immune population for maintaining body homeostasis and warding off foreign pathogens, macrophages display high plasticity and perform diverse supportive functions specialized to different tissue compartments. Consequently, aberrance in macrophage functions contributes substantially to progression of several diseases including cancer, fibrosis, and diabetes. In the context of cancer, tumor-associated macrophages (TAMs) in tumor microenvironment (TME) typically promote cancer cell proliferation, immunosuppression, and angiogenesis in support of tumor growth and metastasis. Oftentimes, the abundance of TAMs in tumor is correlated with poor disease prognosis. Hence, significant attention has been drawn towards development of cancer immunotherapies targeting these TAMs; either depleting them from tumor, blocking their pro-tumoral functions, or restoring their immunostimulatory/tumoricidal properties. This review aims to introduce readers to various aspects in development and evaluation of TAM-targeted therapeutics in pre-clinical and clinical stages.

PI3Kgamma Inhibitor Attenuates Immunosuppressive Effect of Poly(l‐Glutamic Acid)‐Combretastatin A4 Conjugate in Metastatic Breast Cancer

“…[1,2] Therefore, a comprehensive understanding of how the immunosuppressive tumor microenvironment develop is critical and regarded as a promising direction of intervention. [4] Macrophages are known for their vital role in immune defense against the foreign pathogens to prevent tumorigenesis. [3] This versatile cell type displays remarkable plasticity with opposite effects on cell survival, immune responses, and angiogenesis, causing overall pro-or antitumor outcomes.…”

“…[3] This versatile cell type displays remarkable plasticity with opposite effects on cell survival, immune responses, and angiogenesis, causing overall pro-or antitumor outcomes. [4,6] Moreover, the increased infiltration of M2-like TAMs also provides a protumor immunosuppressive milieu by altering recruitment and function of leukocytes, such that it is associated with therapeutic failure and poor clinical prognosis in almost all tumors. [5] However, an increasing number of studies indicated that TAMs skew from proinflammatory M1-like phenotype in early stages of some tumors toward the anti-inflammatory M2-like phenotype in most advanced tumors, promoting the tumor growth, angiogenesis, and metastasis.…”

“…[4] Macrophages are known for their vital role in immune defense against the foreign pathogens to prevent tumorigenesis. [4][5][6] Nevertheless, the mechanisms underlying the modulation of TAMs' phenotype in tumor progression, especially after antitumor therapy is yet to be elucidated. [4,6] Moreover, the increased infiltration of M2-like TAMs also provides a protumor immunosuppressive milieu by altering recruitment and function of leukocytes, such that it is associated with therapeutic failure and poor clinical prognosis in almost all tumors.…”

Multivalent Polymers Displaying M2 Macrophage-Targeting Peptides Improve Target Binding Avidity and Serum Stability

“…4–6 Significant attention has therefore been drawn towards development of anti-cancer immunomodulating therapies targeting M2-TAMs in order to lower the relative M2-to-M1 abundance and restore the tumoricidal microenvironment. 7,8 …”

Induction of Pro-Inflammatory Response via Activated Macrophage-Mediated NF-κB and STAT3 Pathways in Gastric Cancer Cells

“…iNOS and CD163 are the markers of M1 and M2, respectively [15]. It is well known that TAMs typically promote cancer cell proliferation, immunosuppression, and angiogenesis in support of tumour growth and metastasis [16,17]. Numerous studies have shown that cancer tissues with high infiltration of TAMs are associated with resistance to therapies and poor patient prognosis [18,19].…”