Secretion of TAMs and autophagy
TAMs can secrete various immunosuppressive molecules, such as IL-10, TGF-β, and prostaglandin E2 (PGE2), into TME, which results in the induction of immunosuppressive Tregs and facilitates T cell suppression and further suppress antitumor immunity[75]. Based on the secretion of various growth factors, cytokines, chemokines, and extracellular vesicles, TAMs can exert antitumor immune effects and immunosuppressive effects through multiple pathways[76, 77]. Certain substances secreted by TAMs promote autophagy in tumor cells. Research showed that M2 macrophages would secrete IL-17 to stimulate chaperon-mediated autophagy in tumor cells to help them avoid apoptosis[50]. Ni[78] et al. indicated that GDNF secreted by TAMs can regulate lysosomal function and autophagic flux through the GDNF-GFRA1 axis to enhance autophagy levels in GC cells, thus helping TAM colonization and survival in the metastasis. TAMs-exosome H19, because of the increased LC3-II expression and decreased levels of p62, significantly enhanced the autophagy of BC cells by stabilizing the expression of ULK1[79]. This suggests that the secretion of TAMs contained the regulatory effector of autophagy process in cancer cells. The activation of autophagy in TAMs promotes the secretion of inflammatory cytokines and thus increases the tumor-associated inflammatory response, aiding tumor progression[61]. Wang[80] et al. found that induction of autophagy in TAMs, promoting TGF-β1 secretion through the FUT4/p-ezrin pathway and induced EMT in co-cultured lung adenocarcinoma cells. However, some cargo proteins can be secreted through autophagy[25, 26]. For example, Gal-1, a soluble pro-tumor factor widely expressed in TAMs. TAMs can regulate Gal-1 secretion via TLR2-mediated secretory autophagy to facilitate HCC growth in mice and correlates with the poor prognosis of HCC patients[81]. In summary, Autophagy-regulated TAM can promote tumorigenesis and progression by mediating interactions with tumor cells through autocrine or paracrine, activating inflammatory cells, disrupting cytokine networks, and evading immune surveillance.