Introduction
Cancer poses a serious threat to human life and health. Aata from GLOBOCAN 2020[1] show that 19.3 million new cancer cases and 9.9 million cancer deaths occurred worldwide in 2020, with a disease and death rate of 51.3%. The number of cancer cases in China reached 4.57 million, accounting for 24% of the total number of new cancers worldwide, of which the top five cancer types diagnosed were lung, colorectal, gastric, breast, and liver cancers; the number of deaths was about 3 million, accounting for 30% of the total cancer deaths, and the top five cancers leading to death were lung, liver, gastric, esophageal, and colorectal cancers. It is noteworthy that China ranks first in the world in terms of both new cancer incidence and deaths. It is estimated that in 2022, China will have approximately 4.82 million new cancer cases and 3.21 million cancer deaths[2]. However, the form of cancer diagnosis and treatment in China is not optimistic, mainly surgical resection of lesions with radiotherapy and chemotherapy as adjuvant means, but incomplete surgical resection and postoperative recurrence and metastasis may occur, resulting in poor prognosis. Most of the research on cancer focuses on the tumor itself. In fact, the drugs targeting tumors cannot eliminate all the tumor cells in the body, and the remaining part of tenacious tumor cells can further promote the immune microenvironment of the tumor, which eventually leads to the recurrence and metastasis of the tumor. Importantly, tumor cells do not exist alone, but are in a collection known as the TME. The tumor microenvironment[3] is composed of lymphocytes, endothelial cells, tumor-associated macrophages (TAMs), cancer-associated fibroblasts, myeloid-derived suppressor cells, local and bone marrow-derived stem cells, and surrounding stroma, which have an important influence on the growth, proliferation, and metastasis of tumor cells. In the TME, cell-cell interactions and cell-matrix interactions, both directly contacted and indirectly regulated, constitute a complex network system that allows tumor cells to respond to them, such as antitumor immune response and immune escape. Recent studies have clarified the important role of the TME in carcinogenesis and progression, where a series of immunosuppressive cell subsets, inflammatory molecules and signaling pathways mediate immunosuppressive effects, induce tolerance and promote tumor proliferation, invasion and metastasis[4]. Therefore, the study of the role of TME will be an important breakthrough to change the current situation of symptomatic treatment”[5].
In the tumor microenvironment, TAMs are an abundant and active class of infiltrative inflammatory cells, accounting for 50% of infiltrating tumor stromal cells[6], and play an important role in promoting tumorigenesis, metastasis and invasion, angiogenesis, and drug resistance through the secretion of cytokines and chemokines[7-9]. TAMs have two functional states due to the stimulatory signals of the particular microenvironment in which they reside[10], M1 type can secrete pro-inflammatory cytokines, increase tumor antigen presentation, and directly kill tumor cells through phagocytosis, which leads to immune activation, for example, M1 TAM exert anti-tumor immune effects by secreting inflammatory mediators such as IL-6, IL-12, and TNF-α[11]; M2 type promote angiogenesis and tumor development by producing anti-inflammatory cytokines such as IL-10, TGF-β, and IL-13, promote angiogenesis and tumor development, and exert immunosuppressive effects by directly inhibiting cytotoxic T cell function through the expression of programmed cell death ligands PD-L1 and PD-L2[6, 11]. In pancreatic ductal adenocarcinoma, increased secretion of IL-8 by TAMs promotes PDAC cell motility in vitro and metastasis in vivo via the STAT3 pathway, which mediated epithelial-mesenchymal transition in cancer cells[12]. The infiltration of TAMs is significantly increased in patients with bladder cancer, and the secretion of CXCL8 by TAMs promotes the expression of MMP-9, VEGF and E-cadherin in bladder cancer cells, which causes alterations in the migration, invasion and pro-angiogenic capacity of bladder cancer cells, leading to the progression of bladder cancer[13]. For the treatment of breast cancer, TAMs-targeted therapy may improve the efficacy of breast cancer chemotherapy, reverse tumor cell resistance to chemotherapeutic agents, as well as enhance the efficacy of immune checkpoint inhibition in preclinical breast cancer models, while TAM repolarization may also be a potential strategy to improve the efficacy of breast cancer radiation therapy[14]. Apart from that, in the context of relevant cancer studies, TAM PD-1 expression not only negatively correlated with M1 polarization and phagocytosis of tumors by tumor-associated macrophages, but also inhibited neighboring T cells by promoting M2 macrophage polarization in the tumor microenvironment, thereby suppressing neighboring effector T cells and thus impairing anti-tumor immunity[15-17]. In conclusion, TAMs play an important role in tumor development, immunosuppression and mediating therapeutic resistance, and research targeting tumor-associated macrophages holds great promise. Notably, macrophages as immune cells are the first line of defense against infection and have a crucial role in many physiological processes, and the two polarization states of TAMs also play different anti-tumor and tumor-promoting roles in the tumor microenvironment, therefore, antagonizing the tumor-promoting effector molecules produced in TAMs and blocking the signaling pathways would be feasible approaches.
Recently, autophagy has been shown to play a key role in almost all diseases, especially in cancer[18, 19]. Tumor cells always maintain higher levels of basal autophagy compared to normal cells and play an important role in tumor cell survival. Importantly, the role of autophagy in cancer is complex and highly context-dependent[20]. During cancer development and tumorigenesis, autophagy has been found to play a double-edged role in the molecular mechanisms of cancer, i.e., promoting apoptosis or inhibiting apoptosis, thereby affecting tumor cell growth, proliferation, and metastasis, etc. Some studies have established that the dual role of autophagy in tumor progression is closely related to microenvironmental stress and immune system conditions[21]. Therefore, further understanding of the role of autophagy in the tumor microenvironment in cancer is crucial for the corresponding cancer therapy. Autophagy, a process of intracellular degradation, has three main modes of action, namely macroautophagy, microautophagy and molecular chaperone-mediated autophagy (CMA). Macroautophagy, the process of which is achieved by wrapping associated misfolded proteins and damaged organelles within the cell to form autophagic vesicles, which then fuse with lysosomes to achieve degradation, thus allowing the cell to reach homeostasis[22]. Microautophagy refers to the direct uptake of cytoplasmic material into invaginations in the lysosomal and endosomal limiting membrane, which are then pinched off and released as vacuoles to the lumen[23]. CMA is unique as its substrates are not transported to the lysosome by vacuolar import, but by the binding of selected proteins expressing specific targeting motifs to the ubiquitous cytoplasmic protein Hsp70 (heat-shock protein 70) and dock directly onto lysosomal-associated membrane protein-2A (LAMP-2A), which is its unique receptor in the lysosomal membrane for import across the lysosomal membrane and degradation[24]. However, instead of being degraded, some cargo proteins can be secreted through autophagy[25, 26]. Both degradative and secretory autophagy utilize various chemical processes and active substances (e.g. autophagosome formation, ubiquitin), but secretory autophagy does not degrade its cargo through lysosomes; the proteins in the autophagosomes are secreted out after their fusion with the multivesicular bodies (MVBs) to form amphisomes, which are then fused to secretory lysosomes or direct to the plasma membrane to secrete proteins[27], and secretory autophagy mediates the secretion of IL-1β, IL-6, CXCL8,TGF-β, HMGB1, but their regulatory mechanisms need further investigation and will contribute to therapeutic development to counteract the disease and enhance normal physiological functions[27, 28]. However, the results of many in vivo and in vitro experiments have shown that antitumor drugs induce cytoprotective, cytotoxic and cytostatic forms of autophagy in various cancer models, which is an important mechanism leading to the development of drug resistance[29]. And what can be seen is that the multiple roles of autophagy in cancer therapy are of great interest. In this review, we summarize the regulatory role of autophagy in the interaction between TAMs and tumor cells and outline the various signaling molecules and molecular pathways through which these processes occur in order to further understand their significance in cancer, their impact on cancer development, and to provide additional ideas for cancer research.