Besides, the downregulation of the transcription factor signal transducers and activators of transcription (STAT) 3 (STAT3) also promotes monocyte-associated bone marrow-derived suppressor cells to differentiate into mature TAMs ( 13). Meanwhile, resident macrophages surrounded by solid tumors such as lung or brain tumors may also proliferate in situ and infiltrate into TME ( 12). Chemokines secreted by tumor cells or TAMs such as C-C motif chemokine ligand 1(CCL1), CCL2, CCL5, transforming growth factor- β (TGF-β), platelet-derived growth factor, vascular endothelial growth factor (VEGF), and colony-stimulating factor-1 (CSF-1) can recruit monocytes into TME and promote their differentiation into TAMs ( 10, 11). TAMs are important components of infiltrating immune cells in TME, most of which are differentiated from monocytes recruited from the periphery to the tumor site ( 9). Meanwhile, different types of TME, which are composed of distinct species and content of immune cells are also closely related to clinical immunotherapy efficacy ( 8). High levels of extracellular matrix, hypoxia, immunosuppressive cytokines, toxic metabolites, and high expression of immune checkpoint molecules are the main contributors of tumor immune suppression ( 6, 7). In most cases, the anti-inflammatory TME forms immunosuppressive networks that results in immune resistance and ultimately facilitate tumor growth or metastasis ( 5). TME is a highly complex system composed of abnormal vasculatures, dense extracellular matrix (ECM), fibroblasts, tumor-resident immune cells ( e.g., tumor-associated myeloid cells, mast cells, natural killer (NK) cells, tumor-associated macrophages (TAMs), T and B lymphocytes), and various secreted factors ( 3, 4). Tumor microenvironment (TME) with high anti-inflammatory immune cell frequencies and an immunosuppressive network is the culprit responsible for the inefficiency of clinical cancer immunotherapy ( 1, 2). Finally, we conclude with our perspectives on the future development in this field. Moreover, the most recent advances in utilizing nanomedicine for the TAM immunomodulation for augmented cancer immunotherapy are introduced. To help readers better understand this emerging field, the potential TAM reeducation targets for potentiating cancer immunotherapy and the underlying mechanisms are summarized in this review. Recently, efforts have been made to reeducate TAMs from M2- to M1- phenotype to enhance cancer immunotherapy, and great progress has been made in realizing efficient modulation of TAMs using nanomedicines. Evidence suggests that occupation of the TME by M2-TAMs is closely related to the inactivation of anti-tumor immune cells such as T cells in TME. TAMs are generally identified as two distinct functional populations in TME, i.e., inflammatory/anti-tumorigenic (M1) and regenerative/pro-tumorigenic (M2) phenotype. Tumor-associated macrophage (TAM) as an important component of tumor microenvironment (TME) are closely related with the occurrence, development, and metastasis of malignant tumors. 4Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences, Ningbo, China.3Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, Ningbo Hwa Mei Hospital, University of Chinese Academy of Sciences, Ningbo, China.2College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.1Key Laboratory of Novel Targets and Drug Study for Neural Repair of Zhejiang Province, School of Medicine, Zhejiang University City College, Hangzhou, China.Xinyuan Shen 1,2† Shengcheng Zhou 2† Yidong Yang 2 Tu Hong 2 Ze Xiang 2 Jing Zhao 2 Chaojie Zhu 2 Linghui Zeng 1* Lingxiao Zhang 1,2,3,4*
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