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.