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.