Polarization of TAMs and autophagy
Balancing macrophage polarization has been called the ”holy grail” of macrophage-targeted therapy[51]. Since different phenotypes of macrophages maintain plasticity, TAMs in the TME can switch between phenotypes according to different stimulation signals, regulating the polarization status of macrophages in the TME has become one of the current therapeutic research strategies. There is evidence for an important role of autophagy in TAMs polarization and tumor progression[61]. Importantly, M2 macrophages are more affected by autophagy-regulated metabolic responses than M1 macrophages, and therefore autophagy inhibitors will likely serve as a class of drugs used as repolarizing agents for TAMs, thereby improving tumor development[62]. The study indicates a correlation between autophagy inhibition and TAM repolarization, in the Hep-2 laryngeal tumor model in mice, autophagy inhibitor CQ converted the M2-dominated TAM population to an M1-dominated TAM population, and LC3-II expression analysis demonstrated that the TAM repolarization in vivo was associated with a significant reduction of the autophagy level in the tumor tissue[63]. To elucidate how M1 macrophages can be polarized by inhibiting autophagy, Chen et al[64] found that following the administration of the autophagy inhibitor CQ, an increase in macrophage lysosomal pH was measured, and causing Ca2+ release via the lysosomal Ca2+ channel mucolipin-1 (Mcoln1), which induces the activation of p38 and NF-κB and transcription factor EB (TFEB), thus polarizing TAMs to M1 phenotype and reprograming the metabolism of TAMs from oxidative phosphorylation to glycolysis. Similar to CQ, HCQ is a class of autophagy inhibitors that promotes the conversion of M2 macrophages to M1 macrophages and enhances the sensitivity of tumor cells to chemotherapeutic agents when HCQ is used in combination with chemotherapeutic agents. Meanwhile, Li et al[65]demonstrated that HCQ can induce CD8+T cell infiltration into tumor sites to exert anti-tumor effects by increasing the lysosomal pH in cancer cells and fostering the transition of M2-TAMs to M1 macrophages. Notably, when the autophagy inducer rapamycin and the autophagy inhibitor HCQ were combined, M2-like TAM were reprogrammed to an M1-like phenotype by modulating the ratio between the two, and the results showed that decreased macrophage polarization in M2 in vitro and enhanced the intra-tumoral M1/M2 ratio in the intracranial GL261 tumor model after RQ treatment were evident [66]. Through tumor-derived signaling within TME, TAMs can be polarized into a pro-tumor phenotype with immunomodulatory effects. Hepatocellular-derived HMGB1 stimulates NADPH NOX2-reactive oxygen species (ROS) production via TLR2, which triggers autophagy formation and leads to lysosomal degradation of NF-κB p65, thereby maintaining M2 macrophage polarization[67]. H-GDEs induce autophagy of TAMs and promote M2-like macrophage polarization, thereby promoting glioma proliferation and migration in vitro and in vivo[68]. KDELC2, which can stimulate angiogenic factor expression and thus promote tumor neovascularization, mainly by increasing autophagy of glioblastoma cells to promote tumor angiogenesis, and by inducing TAM polarization into M2 macrophages to promote tumor angiogenesis. Inhibition of KDELC2 expression increases TAM activity, which mainly tends to differentiate into M1 macrophages and inhibits glioblastoma angiogenesis[69]. However, the Chinese herbal medicine XSD, in vitro and in vivo, was found to promote the polarization of M2 TAMs to the M1 phenotype by enhancing autophagy in MPE, resulting in the expansion of M1 macrophages and reduction of M2 macrophages, and thus improving clinical symptoms and the quality for life of patients[70]. HMGB1, a secretory autophagy protein, increased secretion from glioblastomas in response to the chemotherapeutic drug temozolomide and promoted M1-like polarization of TAMs, thereby enhancing glioblastoma cell sensitivity to TMZ as well as inhibiting glioblastoma growth[71]. CPT, a drug studied in triple-negative breast cancer, induces autophagy to reset the phenotype of tumor-associated M2 macrophages to the M1 phenotype and ameliorates tumor proliferation via the apoptosis signal-regulating kinase 1 (ASK1) pathway and promotes anaerobic glycolysis in M2 macrophages[72]. This also provides a theoretical basis for further studies on the complex relationship between autophagy, the polarization of tumor-associated macrophages that occur and tumor cell development. It illustrates that the level of autophagy may be an important factor affecting repolarization of TAMs, and cannot promote M2 polarization or M1 repolarization by absolutely inhibiting or inducing autophagy, thus exerting anti-tumor effects. In addition to that,macrophage polarization is not only associated with phenotypic changes (surface markers, cytokines and enzymes) but also reprograms their metabolic patterns. Autophagy promotes mitochondrial respiration, maintains mitochondrial health and provides free fatty acids, M2 macrophages require increased breakdown of FFAs and mitochondrial oxidative phosphorylation to differentiate, whereas M1 macrophages are committed to aerobic glycolysis[62]. It has been reported that the IL-33/ST2 pathway promotes enhanced cellular oxidative phosphorylation through regulation of mitochondrial autophagy to remodel macrophage metabolism, further increasing the expression of M2 polarization genes thereby enhancing M2 polarization in macrophages and ultimately promoting tumor growth[73].
Accumulated studies have demonstrated that targeted TAMs to undergo autophagy-induced changes in polarization status as the primary means, so what effect would autophagy have on TAMs if it is tumor cells that undergo autophagy, and consequently, what effect would it have on tumor progression? It has been shown that autophagosomal TRAP released from tumor cells promotes suppression of T-cell-mediated anti-tumor immune response by inducing M2-like macrophages to promote tumor progression. In Beclin1 knockdown tumor-bearing mice, TAMs with significantly decreased expression of CD206 and PD-L1, as well as slightly increased expression of CD86 and MHC-II, suggesting that inhibition of tumor cell autophagy leads to reprogramming of TAMs from an immunosuppressive M2-like phenotype to an inflammatory M1-like phenotype[74]. It is important to regulate the polarization state of TAMs rather than depleting them in the TME on tumor cell progression, in which the level of autophagy plays a key role and provides ideas and directions for further research.