Conclusions and prospects
Autophagy and TAMs have a dual role in cancer, intricately intertwined
with tumorigenesis, tumor progression, and chemotherapeutic drug
sensitivity, all depending on tumor characteristics and TME, and more
studies are needed for a comprehensive assessment to determine how to
use autophagy modulators and TAMs strategies appropriately. It has been
suggested, first, that inhibition of autophagy regulates infiltration of
TAMs thereby improving drug resistance in tumor cells. However,
knowledge remains limited compared to other autophagic pathways, and
many challenges remain to be addressed. Is the increase or decrease of
TAMs infiltration associated with changes in the number of peripheral
macrophages, allowing for changes in the immune response? Does it
increase infiltration of other stromal cells in the TME and modulate the
antitumor immune response? Second, targeting autophagy of TAMs or tumor
cells can regulate repolarization of TAMs and ameliorate tumor
development, and there are multiple mechanistic studies to support this,
but are the autophagy regulation of TAMs and tumor cells consistent? Can
targeting TAMs or tumor cell autophagic processes promote antitumor
effects more efficiently? In addition to this, new studies have found
that M1-type macrophages also promote malignancy. Does this suggest that
there is a balance between M2 depletion, M1 repolarization and M1/M2
ratio that can make the TME unfavorable for tumor cell development?
Then, autophagy in TAMs is activated to promote the secretion of
multiple immune mediators, which regulates the autophagy of tumor cells
to occur and cause tumor development. However, can these secreted
substances be markers of TAMs or/and TME that have some potential
significance in judging the therapeutic effect of tumor patients? Again,
from the study of TME, TAMs may play a key role in transforming immune
”cold” tumors into ”hot” tumors, and autophagy is also one of the common
processes in immunotherapy, so can the two be rationally linked? Is
there a potential role in improving the efficacy of immunotherapy for
malignant tumors by modulating the level of autophagy between TAMs and
tumor cells? Finally, autophagy plays an important role in the
infiltration, polarization, and secretion of TAMs for the development of
tumor cells. Can the synergistic occurrence of these three aspects be
promoted to improve the sensitivity of tumor cells to anti-tumor immune
responses? In the course of this review, two key points were identified:
autophagy regulation does not correspond to the state of TAMs and the
development of tumor cells in a single way, and is this related to the
different levels of autophagy in different cells? M1 macrophages have
metabolic characteristics more similar to tumor cells, and M2
macrophages are closer to the metabolic state of normal cells. So is
there competition between M1TAM and tumor cells and between M2 TAM and
normal cells? Therefore, we need to investigate more deeply the
molecular regulatory mechanisms of autophagy between TAMs and tumor
cells, and this knowledge will open a new window for the study of
autophagy and TME and, more importantly, will provide new opportunities
for the treatment of related cancers. However, the application of this
strategy to different cancer types and different stages of cancer
development remains context-specific.
Author Contributions: Conceptualization, M.H., J.X.F., and
Z.Y.H.; writing—original draft preparation, M.H.; writing—review,
revise and editing, J.Z. All authors have read and agreed to the
published version of the manuscript.
Funding: This work was supported by the grants from the
National Natural Science Foundation of China (82003380), the Natural
Science Foundation of Chongqing (cstc2018jcyjAX0573,
cstc2020jcyj-msxmX0110) and the Scientific and Technological Research
Program of Chongqing Municipal Education Commission
(KJ202000541975044).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of
interest.
Data Availability Statement: The data used to support the
findings of this study are available from the corresponding author upon
request