Tumor-associated macrophages (TAMs), representing most of the leukocyte population in solid tumors, demonstrate great phenotypic heterogeneity and diverse functional capabilities under the influence of the local tumor microenvironment. These anti-inflammatory and protumorigenic macrophages modulate the local microenvironment to facilitate tumor growth and metastasis. In this review, we examine the origin of TAMs and the complex regulatory networks within the tumor microenvironment that facilitate the polarization of TAMs toward a protumoral phenotype. More extensively, we evaluate the mechanisms by which TAMs mediate angiogenesis, metastasis, chemotherapeutic resistance and immune evasion. Lastly, we will highlight novel interventional strategies targeting TAMs in preclinical studies and in early clinical trials that have significant potential in improving efficacy of current chemotherapeutic and/or immunotherapeutic approaches.

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The programmed death-1 (PD-1) and the PD ligand 1 (PD-L1) interaction represents a key immune checkpoint within the tumor microenvironment (TME), and PD-1 blockade has led to exciting therapeutic advances in clinical oncology. Although IFN-γ–dependent PD-L1 induction on tumor cells was initially thought to mediate the suppression on effector cells, recent studies have shown that PD-L1 is also expressed at high level on tumor-associated macrophages (TAMs) in certain types of tumors. However, the precise role of PD-L1 expression on TAMs in suppressing antitumor immunity within the TME remains to be defined. Using a myeloid-specific Pdl1 -knockout mouse model, here we showed definitive evidence that PD-L1 expression on TAMs is critical for suppression of intratumor CD8 + T cell function. We further demonstrated that tumor-derived Sonic hedgehog (Shh) drives PD-L1 expression in TAMs to suppress tumor-infiltrating CD8 + T cell function, leading to tumor progression. Mechanistically, Shh-dependent upregulation of PD-L1 in TAMs is mediated by signal transducer and activator of transcription 3, a cascade that has not been previously reported to our knowledge. Last, single-cell RNA sequencing analysis of human hepatocellular carcinoma revealed that PD-L1 is mainly expressed on M2 TAMs, supporting the clinical relevance of our findings. Collectively, our data revealed an essential role for Shh-dependent PD-L1 upregulation in TAMs in suppressing antitumor immunity within the TME, which could lead to the development of new immunotherapeutic strategies for treating cancer.

The growth of hematologic malignant cells can be facilitated by other non-tumor cells within the same microenvironment, including stromal, vascular, immune and mesenchymal stem cells. Macrophages are an integral part of the human innate immune system and the tumor microenvironment. Complex interplays between the malignant hematologic cells and the infiltrating macrophages promote the formation of leukemia, lymphoma or myeloma-associated macrophages. These pro-tumorigenic macrophages in turn play an important part in facilitating tumor growth, metastasis and chemotherapeutic resistance. Previous reports have highlighted the association between tumor-associated macrophages (TAMs) and disease progression in hematologic malignancies. This review summarizes the role of TAMs in different subtypes of leukemia, lymphoma and myeloma, focusing on new insights and targeted therapies.

Tumor-associated macrophages (TAMs) represent the most abundant leukocyte population in most solid tumors and are greatly influenced by the tumor microenvironment. More importantly, these macrophages can promote tumor growth and metastasis through interactions with other cell populations within the tumor milieu and have been associated with poor outcomes in multiple tumors. In this review, we examine how the tumor microenvironment facilitates the polarization of TAMs. Additionally, we evaluate the mechanisms by which TAMs promote tumor angiogenesis, induce tumor invasion and metastasis, enhance chemotherapeutic resistance, and foster immune evasion. Lastly, we focus on therapeutic strategies that target TAMs in the treatments of cancer, including reducing monocyte recruitment, depleting or reprogramming TAMs, and targeting inhibitory molecules to increase TAM-mediated phagocytosis.

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Chimeric antigen receptors (CAR) are fusion proteins engineered from antigen recognition, signaling, and costimulatory domains that can be used to reprogram T cells to specifically target tumor cells expressing specific antigens. Current CAR-T cell technology utilizes the patient’s own T cells to stably express CARs and has achieved exciting clinical success in the past few years. However, current CAR-T cell therapy still faces several challenges, including suboptimal persistence and potency, impaired trafficking to solid tumors, local immunosuppression within the tumor microenvironment and intrinsic toxicity associated with CAR-T cells. This review focuses on recent strategies to improve the clinical efficacy of CAR-T cell therapy and other exciting CAR approaches currently under investigation, including CAR natural killer (NK) and NKT cell therapies.