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