The FEBS Journal - 2021 - Rangel - Autophagy and Tumorigenesis

STATE-OF-THE-ART REVIEW
Autophagy and tumorigenesis

Michael Rangel1 , Jerry Kong1, Vrushank Bhatt1, Khoosheh Khayati1 and
Jessie Yanxiang Guo1,2,3
1 Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA
2 Department of Medicine, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA
3 Department of Chemical Biology, Rutgers Ernest Mario School of Pharmacy, Piscataway, NJ, USA
Keywords Autophagy is a catabolic process that captures cellular waste and degrades
autophagy; cancer; cancer metabolism; them in the lysosome. The main functions of autophagy are quality control
cancer treatment; immune response;
of cytosolic proteins and organelles, and intracellular recycling of nutrients
metastasis; p53
in order to maintain cellular homeostasis. Autophagy is upregulated in
Correspondence many cancers to promote cell survival, proliferation, and metastasis. Both
J. Y. Guo, Rutgers Cancer Institute of New cell-autonomous autophagy (also known as tumor autophagy) and non-
Jersey, RBHS-Robert Wood Johnson cell-autonomous autophagy (also known as host autophagy) support
Medical School, Rutgers, The State tumorigenesis through different mechanisms, including inhibition of p53
University of New Jersey, 195 Little Albany activation, sustaining redox homeostasis, maintenance of essential amino
Street, New Brunswick, NJ 08901, USA
acids levels in order to support energy production and biosynthesis, and
Tel: 732-235-9657
inhibition of antitumor immune responses. Therefore, autophagy may serve
E-mail: yanxiang@cinj.rutgers.edu
as a tumor-specific vulnerability and targeting autophagy could be a novel
Michael Rangel and Jerry Kong contributed strategy in cancer treatment.
equally to this article
(Received 14 April 2021, revised 28 June

2021, accepted 15 July 2021)
doi:10.1111/febs.16125
Introduction
Macroautophagy (herein referred to as autophagy) is a dysfunctional or unnecessary cellular components to
major catabolic pathway for the delivery of the lysosome for degradation and subsequent reuse, a
Abbreviations
3-MA, 3-methyladenine; AMPK, AMP-activated protein kinase; ARG1, arginine-degrading enzyme arginase I; ATG, autophagy-related gene;
BECN1, beclin-1; ccRCC, clear-cell renal carcinoma; CNS, central nervous system; CQ, chloroquine; CTL, cytotoxic T lymphocyte; CV,
coxsackievirus; DAMP, danger-associated molecular patterns; DDR, DNA damage response; DRAM, damage-regulated autophagy
modulator; EMT, epithelial–mesenchymal transition; FAO, fatty acid oxidation; FIP200, focal adhesion kinase interacting protein of 200 kDa;
GEMM, genetically engineered mouse model; GM-CSF, granulocyte–macrophage colony-stimulating factor; HCQ, hydroxychloroquine; HGF,
hepatocyte growth factor; ICB, immune checkpoint blockade; IGF1, insulin-like growth factor-1; IL-3, interleukin 3; ISG15, interferon-
stimulated gene 15; isRNA, immunostimulatory RNA; KL, Kras-mutant LKB1-deficient; KP, Kras-mutant p53-deficient; LAP, LC3-associated
phagocytosis; LC3, microtubule-associated protein 1A/1B light-chain 3B; LC3-PE, LC3-phosphatidylethanolamine; LD, lipid droplet; LIR, LC3-
interaction region; MHC, major histocompatibility complex; MNV, mouse norovirus; mTOR, mammalian target of Rapamycin; mTORC1,
mTOR complex 1; NBR1, neighbor of BRCA1 gene 1 protein; NSCLC, non-small-cell lung cancer; PBMC, peripheral blood mononuclear cell;
PDAC, pancreatic ductal adenocarcinoma; PI3K, phosphoinositide 3-kinase; PKB, protein kinase B; PMN, piecemeal microautophagy; PPT1,
palmitoyl-protein thioesterase 1; RHIM, RIP homotypic interaction motif; ROS, reactive oxygen species; RTK, receptor tyrosine kinase; TIM-
4, T-cell immunoglobulin and mucin domain protein-4; TLR, Toll-like receptor; TSC1/2, tuberous sclerosis complex 1/2; ULK1/2, Unc-51-like
autophagy-activating kinase 1/2; Vps34, vacuolar protein sorting 34 complex.
The FEBS Journal 289 (2022) 7177–7198 ª 2021 Federation of European Biochemical Societies 7177
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Autophagy-mediated tumor promotion M. Rangel et al.
process which is conserved from yeast to mammals [1]. The AMPK/ULK pathway
Autophagy is essential for cellular homeostasis, and
AMPK is activated during energy crisis, such as dur-
abnormal autophagy is associated with many human
ing amino acid depletion or glucose deprivation, which
diseases [2]. We will focus on the role of autophagy in
leads to a large AMP:ATP ratio within the cell. More
cancer, and in particular, we will elucidate how autop-
specifically, AMPK is allosterically activated by AMP
hagy regulates the immune response and metabolism
and ADP, while competitively inhibited by ATP.
to support tumor growth and survival.
AMPK, activated during low-charged cellular energy
states, can then phosphorylate ULK1/2, two crucial
Autophagy regulation and machinery mammalian enzymes responsible for stimulating autop-
hagy. Activated AMPK can also coincidentally inhibit
Autophagy is induced by environmental stressors such
mTOR through stimulation of the tuberous sclerosis
as nutrient deprivation. It is negatively regulated by
complex 1/2 (TSC1/2). Hence, AMPK possesses a
the mammalian target of rapamycin (mTOR), a nutri-
unique dual ability to robustly activate autophagy
ent sensor for the cell, and positively regulated by the
within the cell in response to metabolic stress [3].
AMP-activated protein kinase (AMPK), a master reg-
ulator of energy metabolism (Fig. 1) [3].
Autophagy machinery
The PI3K/AKT/mTOR pathway The process of autophagy consists of multiple distinct
steps and is mediated by several autophagy-related
Phosphoinositide 3 kinases (PI3Ks) are a class of
(Atg) genes (Fig. 2). The preliminary step in the for-
enzymes that generate secondary messengers known as
mation of autophagy vesicles is the generation of the
30 phosphoinositide lipids [4]. PI3K enzymes are usu-
ULK complex. The ULK complex consists of a ULK
ally activated by metabotropic G-protein-coupled
family kinase, the focal adhesion kinase interacting
receptors in response to intracellular growth factors,
protein of 200 kDa (FIP200), and autophagy-related
such as insulin-like growth factor-1 (IGF1) or inter-
gene 13 (Atg13) [7]. This complex is doubly regulated
leukin 3 (IL-3) [5]. These 3’ phosphoinositide lipids are
by two important sensors of cellular stress, mTOR and
then able to activate protein kinase B (PKB), also
AMPK. Thus, the ULK complex acts as the main
known as Akt, which phosphorylates downstream tar-
‘gatekeeping’ protein that regulates whether or not the
gets and activates mTOR pathways. More specifically,
autophagic vesicles form.
in nutrient-rich conditions or stimulation by growth
The first and second step of autophagy activation is
factors, Akt activates mTOR complex 1 (mTORC1),
broadly known as the ‘elongation step’ and involves
suppressing autophagy by phosphorylation-dependent
the preparation of autophagic vesicle membranes. The
inhibition of Unc-51-like autophagy-activating kinase
ULK complex first activates the Vps34 complex, which
1/2 (ULK1/2) and the vacuolar protein sorting 34
is composed of Vps34 (a class III PI3K) and Beclin-1
(Vps34) complex [6].
Fig. 1. Autophagy regulatory pathways. The

PI3K/AKT/mTOR pathway, activated by
nutrients and growth factors, leads to
downregulation of autophagy. On the other
hand, the LKB1/AMPK/ULK pathway leads
to upregulation of autophagy due to
metabolic stressors.
7178 The FEBS Journal 289 (2022) 7177–7198 ª 2021 Federation of European Biochemical Societies
M. Rangel et al. Autophagy-mediated tumor promotion
Fig. 2. Autophagy machinery. Step 1, the phagophore is synthesized from ER membrane lipids upon activation by the Vps34 Complex. Step
2, the phagophore is elongated with the help of structural proteins such as LC3 and GABARAP. These Atg8 family of proteins are attached
to the phagophore with the help of ATG complexes. Step 3, p62 and NBR1 serve as cargo receptor proteins that carry polyubiquitinated
proteins destined for degradation to the phagophore. Once the phagophore closes itself around the protein, it is known as an
autophagosome. Step 4, a neighboring lysosome then fuses with the autophagosome to create and autolysosome. Step 5, the
polyubiquitinated protein is degraded using lysosomal enzymes.
(BECN1) [7]. Using the endoplasmic reticulum as a curvature of the phagophore membrane is driven by
base, the Vps34 complex is able to form the autophagic the binding of damaged cargo to receptors lined along
vesicle membrane lipids. These vesicle membranes, the lipid membrane. Eventually, the phagophore com-
known as a ‘phagophore’, generate a spherical vesicle. pletely wraps around the cargo to form a double-
These lipids are then conjugated to microtubule- membrane ‘autophagosome’ [9].
associated protein 1A/1B light-chain 3B (LC3), a Cargo receptor proteins play important roles during
microtubule-associated protein that serves a structural autophagy. p62, also known as sequestosome 1, is a
purpose in vesicle formation [7]. Additionally, LC3 cargo receptor protein that recognizes polyubiquiti-
serves a functional role as a docking site for cargo nated proteins and binds them with autophagosomes.
receptor proteins carrying polyubiquitinated organelles Since most organelles targeted for autophagy are
or proteins. tagged with ubiquitin, p62 plays a crucial role in facili-
There are two ubiquitin-like systems used during tating degradation of these organelles within
phagophore elongation and maturation. The first is autophagosomes [10]. Neighbor of BRCA1 gene 1 pro-
Atg5-Atg12 conjugation, which is mediated by E1-like tein (NBR1) is another cargo receptor protein that
activating enzyme Atg7. The Atg5-Atg12 forms a com- binds polyubiquitinated proteins to autophagosomes.
plex with Atg16 to promote LC3 cleavage by ATG4B Both p62 and NBR1 contain an LIR motif that binds
as well as LC3-phosphatidylethanolamine (LC3-PE) to the Atg8 family of proteins (such as GABARAP
conjugation (the second ubiquitin-like system), which and LC3) found on autophagosomes [11]. Although
is also mediated by Atg7 [8]. It is believed that p62 and NBR1 act similarly, having different cargo
receptor proteins provides a high degree of selectivity essential for sustaining genomic stability [16]. Mito-
in the autophagic process. In other words, having dif- phagy is another important type of cargo-specific
ferent cargo receptor proteins enables damaged orga- autophagy in which damaged and dysfunctional mito-
nelles or protein aggregates to preferentially bind to chondria are selectively captured in autophagosomes
their specific cargo receptor protein. for degradation to ensure mitochondrial quality and
Following these steps, organelle degradation occurs prevent buildup of defective mitochondria [17,18].
when the autophagosomes fuse with lysosomes to form Both nonselective and selective mechanisms of autop-
the ‘autolysosome’. The autolysosome contains the hagy are responsible for the turnover and quality con-
lysosomal enzymes and acidic lumen necessary for pro- trol of several other organelles as well, including
tein degradation [9]. The acidic inner environment that endoplasmic reticulum, ribosomes, centrosomes, and
is generated by this process causes destruction of the lipid droplets [19–23].
inner membrane of the autolysosome but not the outer
membrane. This allows the autolysosome to still retain
Intracellular nutrient recycling
its shape and function [9]. Once degradation is com-
plete, the broken-down contents are released and recy- Autophagy plays an essential role in recycling cellular
cled for subsequent use by the cell [7]. components to maintain metabolism, especially during
metabolic stress such as starvation. Autophagy can
breakdown cytosolic components into amino acids,
Autophagy function
nucleic acids, sugars, and fatty acids, which can then
Autophagy is mainly responsible for the breakdown and be recycled into carbon metabolism for energy home-
recycling of long-lived cell components and cytosolic ostasis and biosynthesis [15,24]. Autophagy is also
organelles and is present in a wide range of organisms responsible for maintaining amino acid levels during
and cell types. Its functions are broad but mainly the neonatal starvation period in mice [25,26], and is
include organelle and protein turnover, tissue remodel- required to maintain glucose homeostasis for adult
ing, and survival during starvation (Fig. 3) [12,13]. mice to survive fasting conditions [27]. Autophagy also
promotes survival in cells undergoing high levels of
metabolic stress, such as rapidly proliferating tumor
Protein and organelle quality control
cells [28–30]. Thus, autophagy provides metabolic sub-
One of the major functions of autophagy is to remove strates required for the growth and survival of both
and degrade damaged cytosolic components such as healthy cells and cancer cells [29,31–33].
protein aggregates and organelles, which enables the
cell to maintain quality control of cellular contents
Noncanonical roles of autophagy proteins
[14,15]. Elimination of toxic protein aggregates or
damaged organelles by autophagy can prevent reactive The proteins involved in autophagy pathways also
oxygen species (ROS) production, making autophagy play noncanonical roles in other cellular contexts.
Fig. 3. Common functions of autophagy.

Autophagy degrades damaged or
dysfunctional cytosolic organelles and
proteins, serving as a quality control and
waste disposal mechanism for the cell.
Autophagy-mediated degradation also
serves as a way for the cell to recycle
nutrients and other substrates for use in
biosynthesis and energy production—
especially during times of stress or
starvation.
Beginning with LC3, there are two different LC3 fam- proteins, such as Atg8 in yeast and LC3 in mammals,
ily members that play a role in cancer cells. LC3C also play noncanonical roles in antiviral immune signal-
plays a tumor suppressive role through regulation of ing. More specifically, IFN production in human
Met/hepatocyte growth factor receptor tyrosine peripheral blood mononuclear cells (PBMCs) is depen-
kinases (Met/HGF RTKs). Met/HGF RTKs are impli- dent on Toll-like receptor 9 (TLR9) trafficking into a
cated in the increased migratory invasive responses of specialized interferon signaling compartment via a LC3-
cancer cells [34]. However, complex formation with associated phagocytosis (LAP) process [43,44].
LC3C selectively degrades these Met/HGF RTKs
through autophagic pathways. Therefore, LC3C plays
Autophagy, the immune system, and
an important role in reducing tumor metastasis. In
cancer
fact, decreased LC3C expression in cancer cells causes
a loss of autophagic degradation of Met/HGF RTKs,
Autophagy in immune cell differentiation
resulting in increased cancer cell invasion and meta-
static progression [34,35]. On the other hand, LC3B is Findings have established a key role of autophagy in
believed to promote tumor growth by initializing a cellular homeostasis and survival, including in immune
survival role for cancer cells once they reach metastatic cells. Monocytes circulating in the blood typically
competence. Tumor microarrays of various cancer undergo apoptosis in the absence of stimulation or dif-
types, such as beast carcinomas and melanomas, have ferentiation. However, in the presence of activating
shown to stain positively for LC3B in moderate to signals such as inflammation, they become viable,
high levels [36]. An explanation for this paradoxical migrate to tissues, and differentiate into macrophages.
role of LC3 is that LC3C reduces metastasis through Autophagy activation is observed in monocytes sur-
selective degradation of Met/HGF RTKs, while LC3B vival and differentiation induced by granulocyte–
promotes metastasis via eliciting autophagy in macrophage colony-stimulating factor (GM-CSF) [45].
response to environmental stressors [36]. Inhibition of autophagy with 3-methyladenine (3-MA),
ATG proteins also play noncanonical functions in chloroquine (CQ), or BECN1 knockdown in mono-
pathogen replication and immune response. For exam- cytes reduces survival, increases apoptosis, and blocks
ple, the Atg5-Atg12 conjugate is crucially involved in macrophagic differentiation and acquisition of phago-
phagophore elongation and maturation. However, stud- cytic functions even when treated with stimulatory fac-
ies show that the Atg5-Atg12 conjugate can also sup- tors [45–47]. Inhibition of the P2RY6-PRKAA1-
press innate immune responses by downregulating type ULK1 pathway blocked both macrophagic differentia-
I IFN production. This is accomplished since the Atg5- tion and autophagy in stimulated cells, suggesting a
Atg12 conjugate can inhibit the function of cytoplasmic mechanism by which differentiation signals induce
RNA helicases responsible for neutralizing virus- autophagy [48]. Thus, autophagy is essential for
derived immunostimulatory RNA structures (isRNA), proper differentiation of monocytes into macrophages.
such as double-stranded RNA or 5’-triphosphorylated
RNA [37]. In fact, mouse embryonic fibroblasts defi-
Autophagy in pathogen clearance
cient in Atg5 and/or Atg12 have shown hyperproduc-
tion of type I IFNs in response to isRNA structures, Within the immune system, one of the main routes of
affirming the Atg5-Atg12 conjugate’s role in suppressing pathogen removal from tissues is phagocytosis and
innate immune responses to viral replication [38]. In degradation. However, several intracellular pathogens
response to mouse norovirus (MNV) infection, instead have adapted mechanisms to evade destruction such as
of inducing autophagy, IFN-gamma-activated phago- blocking lysosomal degradation or migrating out of
cytes recruited Atg5-Atg12-Atg16L1 conjugate to sup- phagocytic vesicles into the cytosol [46]. When typical
press expression of MNV polymerases, thereby phagocytic pathways fail to clear pathogens, autop-
inhibiting the viral replication complex [39,40]. Other hagy’s function in degradation of cytosolic cellular
studies have shown that decreasing levels of Atg13 and components makes it well-suited to target pathogens
FIP200 have led to reduced viral replication of that escape phagocytic vesicles and replicate in the
encephalomyocarditis virus, two picornaviruses, and cytoplasm [49]. Autophagy also enhances phagocytic
coxsackievirus (CV) B3, although an exact mechanism pathways to clear pathogens [50–52]. LC3-associated
of action remains to be elucidated [41]. In addition, phagocytosis (LAP) is a noncanonical form of autop-
FIP200 suppresses immune checkpoint therapy hagy where the core autophagy pathway component
responses in breast cancers by limiting AZI2/TBK1/IRF LC3 conjugates to phagosomes [53]. LAP plays an
signaling [42]. Finally, the Atg8-related family of important role in regulating inflammatory responses
and clearing cell debris, and it is required for clearance Non-cell-autonomous autophagy inhibits Type I
of Aspergillus fumigatus infection [50,52]. LAP is also and II IFN response
involved in the elimination of apoptotic cells by
Non-cell-autonomous autophagy outside of the tumor
macrophages in a process known as efferocytosis to
microenvironment can inhibit an antitumor immune
dampen proinflammatory responses [50,52]. Interferon-
response [67]. In particular, autophagy-mediated ‘hep-
stimulated gene 15 (ISG15) recruits LC3 to phago-
atic autophagy immune tolerance’ is sufficient to inhi-
somes for the IFN-gamma mediated restriction of
bit antitumor T-cell responses against tumor growth.
Toxoplasma gondii infection, which involves engulf-
Systemic or liver-specific Atg7 or Atg5 ablation results
ment of the parasite through LAP. This shows that
in mtDNA release, upregulating IFN type I and II
ISG15 serves as one of the functional links connecting
responses and antigen presentation. This increased
LAP and phagocytosis in host defense, suggesting its
immune response leads to reduced tumor growth,
importance for future studies [54].
which was restored by the loss of IFN-c or STING
[67]. Overall, non-cell-autonomous autophagy pro-
Autophagy suppresses inflammation motes tumor growth by reducing IFN levels and regu-
lating the antitumor immune response.
Autophagy is a potent anti-inflammatory process that
inhibits inflammasome activation and modulates type I
interferon responses [55,56]. The interaction between Autophagy inhibits antigen presentation
autophagy and inflammation is complex and mediated
Antigen presentation is a critical process responsible
by a number of mechanisms. Autophagy degrades
for the body’s adaptive immune response against can-
proinflammatory signaling molecules and regulates
cer growth. The primary responsibility of T cells, both
inflammatory responses from innate immune cells [57].
CD8+ cytotoxic (CTLs) and CD4+ helper (Th cells), is
Autophagy also inhibits inflammation through regula-
to recognize foreign protein antigens docked on major
tion of inflammasome complexes, which are required to
histocompatibility complexes (MHCs) on the surface
process and activate proinflammatory signals such as
of malignant cells [68]. However, cancers can evade
procaspase 1 or pro-IL-1b [58]. Additionally, autophagy
such immunity by immunodominance, display of
is a key regulator of RIP homotypic interaction motif
immune checkpoints, or immunoediting for loss of
(RHIM) domain proteins, which are molecules impor-
specific tumor antigens [69].
tant for inflammatory signaling and cell death. Indeed,
The proteasome plays an essential role in immune
defective autophagy causes a decrease in turnover in
surveillance mechanisms by generating peptides from
RHIM domain proteins in cells, leading to an increase
intracellular antigens that are then ‘presented’ to T
in necroptosis and inflammatory signaling [59]. Defec-
cells [70]. Autophagy has also been identified as a
tive mitochondrial function is associated with accumula-
route to display antigens on MHC class II molecules
tion of ROS inside the cell as well as inflammasome
to CD4+ T cells and is implicated in MHC class I
activation, suggesting that impaired mitochondrial qual-
cross-presentation of tumor antigen and the activation
ity control as a consequence of autophagy inhibition
of CD8+ T cells [71,72]. The expression of MHC I is
could be another mechanism connecting autophagy and
commonly low in pancreatic ductal adenocarcinoma
inflammasome activation [60].
(PDAC), leading to defective antigen presentation that
Autophagy has the paradoxical effects of promoting
prevents T-cell-mediated tumor killing. MHC I mole-
tumor survival while also suppressing initiation of new
cules are selectively targeted for lysosomal degradation
tumors [61]. A typical inflammatory response con-
by an autophagy-dependent mechanism that involves
tributes to increased cell proliferation, cell survival, cell
NBR1 [72]. Autophagy inhibition by genetically
migration, and angiogenesis, which are critical in wound
knocking-out essential autophagy genes or pharmaco-
responses [62]. However, the upregulation of these pro-
logically using autophagy inhibitors such as CQ results
cesses in conjunction with the metabolic stress and
in enhanced antigen peptide presentation, higher levels
DNA damage resulting from production of ROS that
of T cells producing proinflammatory cytokines, such
occurs in persistent and chronic inflammation con-
as IFN-c and tumor necrosis factor (TNF), along with
tribute to tumorigenesis [62–66]. Therefore, suppression
overall lower metastatic burden [72]. An effective strat-
of inflammation is a mechanism by which autophagy
egy of synergizing autophagy inhibitor drugs with dual
inhibits tumor initiation. This effect is contrast to
immune checkpoint blockade (ICB) therapy (anti-PD1
autophagy’s protective role in existing tumors and
and anti-CTLA4 monoclonal antibodies) shows great
demonstrates that the role of autophagy in cancer is
promise at stemming PDAC metastasis [72]. Similarly,
context dependent.
autophagy inhibits MHC I presentation in Kras- limiting T-cell recruitment and activation of the TBK1-
mutant, Lkb1-deficient (KL) lung cancer cells. Upon IFN signaling axis [42].
treatment with autophagy inhibitors, such as CQ or
ULK1 inhibitors MRT68921, KL cells show restored
Autophagy supports Treg lineage stability and
sensitivity to host immune responses due to enhanced
survival fitness, while preventing treg infiltration
immunoproteasome activity and restoration of antigen
into tumors
processing [73]. As a result, autophagy inhibition
increases the sensitivity of KL tumors to anti-PD-1 Regulatory T cells (Tregs) are characterized by the
therapy [73]. expression of the master transcription factor forkhead
T-cell immunoglobulin and mucin domain protein-4 box protein p3 (FoxP3). FoxP3 expression in Tregs is
(TIM-4), which is expressed on myeloid cells, regulates crucial for reinforcing Treg functional integrity and lin-
T-cell homeostasis, thereby impacting host immunity eage stability [79]. In tumor immunity, FoxP3+ Tregs
within the tumor microenvironment. TIM-4 is induced can promote the development and progression of tumors
on tumor-infiltrating myeloid cells by tumor-derived by preventing effective antitumor immune responses in
danger-associated molecular patterns (DAMPs), which tumor-bearing hosts [80]. Autophagy acts as a central
subsequently interacts with AMPKɑ1 and activates and intrinsic regulator of Treg cell maintenance and
autophagy. Autophagy activation impedes tumor anti- immune homeostasis. Deletion of Atg7 or Atg5 specifi-
gen presentation, leading to impaired antitumor cally in Treg cells results in increased apoptosis and
immunity [3]. Therefore, targeting the TIM-4- impaired lineage stability characterized by the loss of
AMPKa1 interaction could be a unique strategy for FoxP3 expression. Thus, autophagy in Tregs acts to sup-
augmenting antitumor T-cell responses in tumor port their functionality and stability. Mechanistically,
microenvironment. autophagy protects Treg cell stability by restraining
Besides regulating antigen presentation in tumor mTORC1-dependent c-Myc expression and function
cells, autophagy supports proper antigen phagocytosis [79]. Treg infiltration in tumors has been associated with
and presentation to MHC class II via modulation of adverse prognosis of cancer patients. In FoxP3CreAtg7fl/
fl
CD36 in dendritic cells [74]. Moreover, autophagy is mice inoculated with MC38 colon adenocarcinoma
involved in B-cell polarization and presentation of par- cells, tumor growth was severely inhibited [79,81].
ticulate antigens [75]. While autophagy ablation within Tregs leads to their
impaired lineage stability, autophagy inhibited in cer-
tain cancers leads to a distinct immune response. In a
Autophagy negatively regulates cytotoxic T
genetically engineered mouse model (GEMM) for
lymphocytes
Kras-driven non-small-cell lung cancer (NSCLC), con-
IFN-c resistance is a conserved tumor cell-autonomous ditional deletion of Atg5 in tumors markedly increased
mechanism of CTL evasion in cancer. Autophagy numbers of FoxP3+ Tregs infiltrating the lung tumor
within various cancer cells, such as renal and breast [82]. It has also been shown that late metastatic lung
carcinomas, acts as a cell-autonomous negative regula- cancers treated with autophagy inhibitors such as CQ
tor of CD8+ T-cell metabolism and antitumor immu- trigger upregulation of CD4+, Foxp3+ tumor-
nity [76,77]. A combination of mapping cytokine- and infiltrating lymphocytes in late metastatic lung cancer
CTL-based genetic interactions and in vivo CRISPR tissues, leading to the induction of chemosensitization
screens identified that autophagy is a conserved media- to carboplatin, immune activation, and cell cycle arrest
tor of both evasion of CTLs by cancer cells and resis- [83]. Thus, data from these studies point to the role
tance to cytotoxicity induced by the cytokines IFN-c that autophagy could prevent FoxP3+ Treg lympho-
and TNF. Such regulation occurs through the cyte infiltration in tumor microenvironment.
autophagy–NF-jb axis. Both genetic ablation (by Tumor cells deploy multiple mechanisms to escape
Atg12 deletion) and pharmacological inhibition (using from immunosurveillance. Autophagy promotes tumor
the VPS34 inhibitor autophinib) to block autophagy immune tolerance and tumor growth via hepatic
sensitized cancer cells to TNF-induced CTL-mediated autophagy-mediated suppression of STING and IFN-c
cell death [77]. Ablation of FIP200 in mice resulted in activation, reduction of antigen presentation, inhibi-
defective autophagy, increased production of chemoki- tion of cytotoxic T-cell infiltration, and enforcing func-
nes in tumor cells, increased infiltration of effector T tional integrity of Tregs. However, autophagy ablation
cells in the tumor microenvironment, and reduced in certain cancers/settings has also shown to increase
mammary tumorigenesis [78]. Moreover, a noncanoni- Treg infiltration, which could increase the sensitivity to
cal autophagy function of FIP200 is responsible for chemotherapy (Fig. 4).
Fig. 4. Autophagy modulates immune response for tumor progression. (A) Non-cell-autonomous autophagy supports immune evasion for
tumor growth. Hepatic autophagy suppresses STING and IFN-c activation to prevent tumor killing by T cells [67]. (B) Cell-autonomous
autophagy promotes tumor growth via 1) reduction of antigen presentation [71,72] and 2) inhibition of cytotoxic T-cell infiltration into the
tumor [76,77]. In certain types of lung cancers, 3) ablation of autophagy has been shown to activate regulatory T cells, thus promoting
tumorigenesis [82,83].
Autophagy and cancer metabolism may arise out of the role of autophagy in sustaining
mitochondrial metabolism, which is critical for cancer
Cancer cells alter their metabolism to meet metabolic cell survival and tumorigenesis, through mitophagy
demands of high proliferation, malignance, and metas- and recycling of substrates for the TCA cycle [89,90].
tasis. Recent studies using genetically engineered Autophagy ablation significantly reduced mitochon-
mouse models (GEMMs) demonstrate that autophagy drial respiration and ATP production during starva-
supports different types of tumor growth through dis- tion, leading to fatal nucleotide depletion, which was
tinct mechanisms, including both cell-autonomous (tu- rescued by exogenous glutamine supplementation [29].
mor cell-intrinsic) and non-cell-autonomous (host) This suggests that glutamine recycled through autop-
autophagy [28,30,84–88] (Fig. 5). hagy is essential to maintain proper mitochondrial
function for energy production and homeostasis.
Tumor cell-intrinsic autophagy supports tumor Autophagy-defective tumor cells also accumulate struc-
growth turally abnormal mitochondria and exhibit other
defects in mitochondrial respiration [84]. Autophagy is
Autophagy maintains energy homeostasis thus required for proper mitochondrial function and
Autophagy is known to promote cell survival through tumor cell metabolism under conditions of metabolic
a number of cell-autonomous mechanisms such as mit- stress.
igating metabolic stress, in part by recycling intracellu-
lar components to provide substrates for metabolic Autophagy regulates lipid metabolism
and biosynthetic pathways [29,33]. Pulse-chase studies
with isotope-labeled nutrients revealed that autophagy Fatty acids are essential metabolic intermediates for
is essential to maintain levels of amino acids when can- several biosynthetic pathways, and in cancer cells,
cer cells are starved [29]. This ‘autophagy addiction’ continuous fatty acid synthesis is required for
Fig. 5. Autophagy Supports Cancer Cell Metabolism (A) Ablation of cell-autonomous autophagy in tumor cells leads to a variety of
outcomes: 1) lowered levels of amino acids, ATP production, and nucleotides synthesis due to reduced substrate recycling [29,89,90], 2)
defective FAO and increased sensitivity to FAO inhibition [28,30], 3) p53 induction [28,95–97], and 4) higher basal ROS levels [29]. (B)
Ablation of non-cell-autonomous autophagy causes various outcomes in the host and the TME: 1) Ablation of host autophagy or liver
autophagy causes the release of arginase I from hepatocytes, thereby reducing circulating arginine that is essential for tumor growth [31], 2)
ablation of systemic autophagy also leads to deduced metabolites in the TME, leading to tumor death [31], 3) ablation of systemic
autophagy is associated with reduced mTOR activity, impairing tumor growth [27,31], and 4) ablation of autophagy in stromal cells of PDAC
restrains the supply of metabolites to tumor cells [33]. Figure template taken from BioRender.com [168].
proliferation and maintaining metabolism [91]. deficient neural stem cells and a reversal of neural
Autophagy-deficient Kras-mutant p53-deficient (KP) defects [92].
lung tumors show increased lipid droplet (LD) accu-
mulation due to defective lipophagy and impaired
Autophagy inhibits p53-mediated tumor suppression
fatty acid oxidation (FAO) [28]. However, in Kras-
driven Lkb1-deficient (KL) lung tumors, autophagy p53 is a well-known tumor suppressive gene that inhi-
ablation upregulates lipolysis, and autophagy-deficient bits tumor growth through several mechanisms, and
cancer cells rely more on FAO to survive starvation there is growing evidence for tumor-promoting interac-
compared to autophagy intact cells. This has shown tions between p53 and autophagy. Under nutrient
to lead to excessive FAO and energy crisis from deprivation, AMPK activation induces p53 activation
depletion of LDs [30]. Despite exhibiting paradoxical [93]. Subsequently, induction of p53 activates the tran-
responses to autophagy deficiency, both autophagy- scription of genes involved in autophagy activation or
deficient KP and KL tumor-derived cell lines are sig- induces autophagy via transcriptional activation of
nificantly more sensitive to FAO inhibition during damage-regulated autophagy modulator (DRAM-1) in
starvation as well as starvation-induced cell death human and mouse cell lines [94]. On the other hand,
compared with autophagy competent cells [28,30]. in various mouse models, p53 induction was observed
Interestingly, inactivation of autophagy by FIP200 when autophagy was ablated, suggesting that autop-
ablation reduced fatty acid release from LDs, result- hagy also regulates p53 and may serve as a resistance
ing in decreased mTORC1 hyperactivation in TSC- mechanism against p53 activators [95].
In normal cells, autophagy protects tissues from production during metabolic stress, and these are all
damage resulting from p53 overactivation, but in functions that promote tumor cell survival.
tumor cells this same function prevents p53-induced
apoptosis and promotes tumor cell survival. p53 induc-
tion was observed in Atg7-deficient Kras-driven lung Autophagy prevents genomic instability
tumors, accompanied by accumulation of defective While autophagy may play a tumor-promoting role as a
mitochondria, reduction of tumor burden, and sup- survival pathway for tumor cells, it also acts as a sup-
pression of cell proliferation. This suppression was pressor of tumor initiation. The metabolic stress caused
partially relieved by the deletion of p53 [28]. This is by starvation or other stressors can induce DNA dam-
supported by similar findings in models of PALB2- age and chromosomal instability. Autophagy-
associated breast cancer, where autophagy ablation competent cells can mitigate this metabolic stress and
reduced tumorigenesis in wild-type models but not in limit genomic instability [108]. However, in autophagy-
models with p53 conditionally deleted [96]. Thus, deficient cells, an accumulation of oncogenic mutations
autophagy promotes tumorigenesis by inhibiting p53- resulting from metabolic stress can serve to promote
mediated tumor suppression [97]. chromosomal abnormalities and tumorigenesis [16].
This conclusion is complicated by findings that in Treatment of cells with an autophagy inhibitor led to
p53-deficient mice containing oncogenic KRAS, autop- elevated levels of micronuclei, a sensitive indicator of
hagy inhibition accelerates pancreatic tumor growth, genomic instability and DNA damage [109]. Hence,
suggesting that the role of autophagy in pancreatic autophagy can suppress tumor initiation by suppressing
tumor progression is context dependent on the status known inducers of genomic instability and tumor initia-
of p53 in tumor cells [98]. On the other hand, another tion, such as reactive oxygen species (ROS), tissue dam-
study showed contradictory findings in which autop- age, and inflammation [15].
hagy deletion in the setting of p53 loss impaired pan- Several nontraditional autophagy functions repre-
creatic tumor progression [99]. These studies utilized sent mechanisms by which autophagy plays an impor-
different models of p53 deletion which could have con- tant role in maintaining genomic stability. Through
tributed to conflicting results. Overall, the interactions noncanonical piecemeal microautophagy (PMN), cells
between autophagy and p53 are complex and further can specifically remove parts of the nuclei containing
investigation can elucidate the role of these interac- damaged DNA to mitigate effects of oxidative stress
tions in various cancers. [105]. Autophagy is also linked to the DNA damage
response (DDR) in a number of ways, such as induc-
Autophagy attenuates oxidative stress tion of AMPK by DDR, suggesting that autophagy
plays a role in maintaining genomic stability through
ROS are constantly generated in the cell from a num- DNA repair [110,111]. Autophagy is required for the
ber of processes including cellular respiration, and selective degradation of RNA granules containing
excessive levels of ROS result in oxidative stress that localized retrotransposon replication intermediates.
can interfere with vital functions [100]. Due to differ- Retrotransposons are a major source of genetic varia-
ences in metabolism from normal cells, including tion chromosomal instability, and mice lacking essen-
increased mitochondrial dysfunction, cancer cells have tial autophagy genes accumulate both retrotransposon
elevated levels of ROS, which if unmitigated can lead RNA and genomic insertions [112]. Appropriative acti-
to damage to cellular components and induce cell vation of RhoA GTPase is essential in proper cytoki-
death [101,102]. Autophagy is activated in response to nesis at the end of mitosis, and autophagy-deficient
ROS production and oxidative stress, suggesting that cells demonstrate cytokinesis failure, chromosomal
it plays an antioxidant role, particularly in tumor cells instability, and multinucleation [113].
[103–105]. Indeed, Atg7-deficient tumor cells showed
higher basal ROS levels in nutrient-rich conditions and
even higher levels in starvation conditions, which was Host autophagy supports tumor growth
attenuated by glutamine supplementation [29]. Mito-
Autophagy maintains circulating arginine
chondrial dysfunction leads to elevated ROS produc-
tion, so autophagy’s role in organelle quality control Tumor survival heavily relies on a variety of circulat-
and clearance of dysfunctional mitochondria is also ing nutrients present in the host bloodstream. Besides
important to mitigate oxidative stress [106,107]. Thus, tumor-intrinsic autophagy, systemic host autophagy is
autophagy is required to sustain redox balance, main- indispensable for tumorigenesis [27,31]. Systemic abla-
tain mitochondrial function, and suppress ROS tion of autophagy leads to the depletion of a number
of amino acids and other essential metabolites in The tumor microenvironment also provides exoge-
serum, including leucine, arginine, and methionine, nous signals to promote tumor autophagy during times
some of which are essential for mTORC1 activation of starvation. For RAS-driven Drosophila me-
[27,31,95,114–116]. Indeed, acute, systemic deletion of lanogaster cancer models, the release of TNF or IL-6
Atg7 or Atg5 impaired tumor growth, which was by starving tumor cells into the microenvironment
accompanied by reduced mTOR activity [27,31]. acted as exogenous signals to induce autophagy, both
Among the altered circulating metabolites caused by in the microenvironment and in the distal tissues. Nor-
the loss of autophagy, reduction of serum arginine mal epithelial cells are engaged as an active part of the
levels is the most striking [27,31]. ‘Arginine-auxotroph’ microenvironment by providing amino acids, support-
tumors are particularly sensitive to depleting arginine ing tumor proliferation [118]. Moreover, allografted
levels and are characterized by their lack of expression tumor implants placed into autophagy-deficient and
for argininosuccinate synthase, which furthers their control models demonstrated poorer tumor growth in
dependence on environmental arginine [31]. Systemic autophagy-deficient models, regardless of where in the
or liver-specific autophagy ablation leads to liver dam- body the tumor was implanted. Tumor growth can
age, which triggers the release of arginine-degrading subsequently be rescued if the tumor implants are
enzyme arginase I (ARG1) from the liver into the transplanted into a model where autophagy is sus-
serum and causes the degradation of arginine to tained [118]. Thus, systemic autophagy plays a major
ornithine. Dietary supplementation of arginine to the role in determining growth, regardless of tumor loca-
autophagy-deficient host or liver-specific autophagy- tion or primary tumor microenvironment.
deficient host partially restored levels of circulating
arginine and rescued tumor growth [31].
Autophagy and metastasis
While autophagy is known to promote tumor cell sur-
Autophagy provides nourishment in the tumor
vival through a number of mechanisms, the role of autop-
microenvironment
hagy in cancer metastasis is also being examined in depth.
Not only do tumor cells rely on host metabolites for Emerging evidence indicates that autophagy is upregu-
nutrition, but the tumor microenvironment also serves lated during tumor metastasis and suggests that autop-
as a potent source of nourishment for cancer cells. hagy promotes several key processes during metastasis.
Tumor microenvironment is composed of endothelial In general, autophagy’s importance in cellular survival in
cells, fibroblasts, inflammatory cells, extracellular response to metabolic stress makes it well-suited to pro-
matrix, cytokines, and growth factors, which support mote metastasis, where tumor cells must survive and
commencement and progression of many types of adapt to altered extracellular conditions [119]. The transi-
tumors. Pancreatic cancer has a robust stromal com- tion of epithelial to more mobile and invasive mesenchy-
ponent that damages vasculature, thereby creating a mal cells through the epithelial–mesenchymal transition
nutrient poor environment. Acute, systemic expression (EMT) often occurs during embryonic development,
of a dominant-negative ATG4b in mice led to regres- wound healing, and the early stages of metastasis [120].
sion of KRAS-driven pancreatic cancer, which is Induction of autophagy promotes EMT through TGF-
caused by the elimination of autophagy-dependent beta-dependent signaling, while ablation of autophagy
metabolic cross-talk between tumor cells and nearby diminishes EMT and cancer cell invasiveness—which can
stromal cells [33]. Autophagy activation in stromal- be rescued through addition of recombinant TGF-beta
associated pancreatic stellate cells promotes the secre- [121]. A recent study suggests that autophagy may pro-
tion of alanine and other amino acids into the tumor mote EMT through myeloid cell activity, a hypothesis
microenvironment to provide substrates to neighboring supported by findings that myeloid-specific autophagy
PDAC cells for lipid and protein biosynthesis [32,33]. ablation decreased tumor cell invasiveness, suppressed
The tumor microenvironment is also associated with EMT, and reduced TGF-beta production [122]. In addi-
an increase in macrophage levels, possibly due to immune tion to directly promoting tumor metastasis and invasive-
responses that aim to clear dying tumor cells [33]. The ness, autophagy plays a key role in enabling malignant
inflammatory effects of these macrophages can be sup- cancer cells to enter a reversible dormant state and then
pressed via activation of LAP in the myeloid compart- reactivate at a later time [123]. These cells are often resis-
ment of the tumor microenvironment, which additionally tant to cancer treatments which tend to target actively
aims to suppress surrounding T lymphocytes [117]. Inhi- proliferating tumor cells. Through a number of mecha-
bition of LAP consequently provides a potential avenue nisms, autophagy promotes not only cancer cell survival
for augmenting the antitumor effects of T lymphocytes. but also metastasis and treatment resistance [124].
Though autophagy seems to promote cancer metas- autophagy can enhance patient outcomes when com-
tasis through a number of mechanisms, several studies bined with current treatments [128].
show that autophagy suppresses growth of migratory
tumor cells into lethal macrometastases [125]. In a
Autophagy inhibition combined with MAPK/ERK
GEMM with transplanted tumor cells, the size of
inhibitors
metastatic lesions was significantly increased in mice
with defective autophagy compared to controls. Inter- RAS proteins are central mediators downstream of
estingly, results from the study indicate that autophagy growth factor receptor signaling and are critical for
only meaningfully suppressed metastasis in the initial cell proliferation, survival, and differentiation. In addi-
stages of outgrowth [126]. Surprisingly, pharmacologi- tion, RAS mutations are frequently detected in many
cal inhibition of autophagy in CQ does not result in types of cancers [129,130]. Therefore, targeting compo-
enhanced tumor metastasis. This may be explained by nents of the Ras-mediated MAPK cascade, also
the fact that in CQ treatment, autophagosomes still known as the RAF/MEK/ERK pathway, is an attrac-
form since core autophagy machinery is functional, tive strategy in the development of novel therapeutic
but after CQ treatment NBR1 remains sequestered in approaches to treat RAS-driven cancers [131]. With a
undigested autophagosomes [127]. This hypothesis is near 100% KRAS mutation frequency, PDAC is con-
supported by the finding that preventing cytoplasmic sidered the most RAS-addicted of all cancers [132]. In
accumulation of NBR1 in autophagy-deficient tumor particular, the RAF/MEK/ERK pathway is central to
cells reversed increases in metastasis [126,127]. Autop- the initiation and maintenance of PDAC [133].
hagy is a pleiotropic cellular process with a number of Attempts have been made to treat PDAC through the
diverse and seemingly contradictory effects, and its use of ERK/MAPK pathway inhibitors. However,
elucidation can aid in the development of new and such treatments generally fail to produce durable
more effective therapeutics. responses in patients [134], indicating that cancer cells
develop inhibitor bypass mechanisms that limit the
effectiveness of this approach.
Autophagy and cancer treatment
A combinatorial siRNA approach to simultaneously
Given the significant role autophagy plays in tumor target multiple genes in KRAS-driven cells showed that
progression and the effects of its ablation on tumor targeting BRAF and CRAF in combination with Atg7 is
survival, autophagy has been explored as a key target a promising therapeutic approach for RAS-driven can-
for cancer treatments (Fig. 6). The modulation of cers [135]. One possible reason for this is that the
Fig. 6. Autophagy in cancer treatment.

Autophagy inhibition in combination with
other cancer treatments can potentiate
overall treatment effectiveness and
overcome resistance. One common cancer
treatment involves the use of RAS/RAF/
MEK/ERK pathway inhibitors, but tumor
cells can adapt resistance to this
therapeutic strategy. ERK inhibition can
partially downregulate mTOR activity,
leading to de-repression and activation of
d
protective autophagy, which may partially
explain tumor adaptation to ERK pathway
c inhibitors such MEK inhibitors. Combining
c an ERK inhibitor with both autophagy
s inhibition and mTOR inhibition can therefore
overcome resistance pathways and increase
overall response to these treatments.
inhibition of the RAF/MEK/ERK pathway activates aberrantly activated in cancers. mTOR-based targeting
autophagy as a survival response to ERK inhibition, strategies exhibit potent anticancer effects in many pre-
which is supported by findings that genetic or pharma- clinical models. However, development of resistance
cological inhibition of autophagy enhanced the antitu- can occur, which limits its success in the clinic
mor activity of ERK inhibition in KRAS-driven PDAC [142,143]. There are multiple mechanisms underlying
[133,136,137]. ERK pathway inhibition is also associ- resistance to mTOR inhibitors, including the rewiring
ated with decreased mTORC1 signaling, and since of metabolic pathways [143]. Autophagy activation is
mTOR activity regulates autophagy activation, inhibi- tightly regulated by mTOR, so induction of autophagy
tion of ERK leads to a de-repression of autophagy by mTOR inhibitors may lead to the drug resistance
[138,139]. This is consistent with findings that ERK inhi- and survival of cancer cells. Therefore, studies of
bition elicits autophagy as a protective survival mecha- mTOR inhibitors combined with autophagy inhibitor
nism and may explain resistance to ERK inhibition HCQ have been tested in several different cancer
based treatment [136] types. Myeloma cells treated with both cyclophos-
Inhibition of MEK and autophagy had antiprolifer- phamide and rapamycin have shown to ‘doubly’
ative effects against PDAC cells both in vitro and in induce autophagy dependence, providing a more
mice xenografted tumors [138]. This antiproliferative robust platform for HCQ to work on [144]. Moreover,
effect of combined ERK pathway and autophagy inhi- multiple patients experienced prolonged stable disease
bition persisted for other cancer types including mela- and less adverse growth rates; however, it is not to the
noma and colorectal cancer [136,140]. Combinational degree that would provide any meaningful effect on
treatment of MEK inhibitor trametinib with autop- patient outcomes [144]. In patients with clear-cell renal
hagy inhibitor hydroxychloroquine (HCQ) in a human carcinoma (ccRCC), treatment with the mTOR inhibi-
patient with PDAC even resulted in a partial but tor everolimus along with HCQ was seen to prolong
nonetheless striking disease response [136,137]. stable disease [145]. mTOR inhibitor temsirolimus,
Pediatric central nervous system (CNS) tumor cells when combined with HCQ, has been proven to be safe
with BRAF(V600E) (but not wild-type) cells display and tolerable in a phase I clinical trial of patients with
high rates of induced autophagy, are sensitive to phar- either advanced solid malignant tumors or metastatic
macologic and genetic autophagy inhibition, and show melanoma. In fact, a median of 3.5 months of PFS
synergy when the clinically used autophagy inhibitor was achieved in approximately 68% of the melanoma
CQ was combined with the RAF inhibitor vemu- patients [146]. A HCQ dose of 600 mg twice daily in
rafenib or standard chemotherapeutics [141]. A patient combination with a temsirolimus dose of 25 mg
with BRAF-mutant brain cancer who had progressed weekly was ultimately recommended as approximately
while on anti-BRAF therapy experienced more than 67% of solid tumor patients and 74% of melanoma
2.5 years of disease regression on a combination of patients achieved stable disease with this dosing regi-
CQ plus a BRAF-targeted therapy [141]. Hence, men [146].
autophagy inhibition in combination with or RAF/
MEK/ERK pathway inhibitors presents promising
Autophagy inhibition combined with
possibilities for future therapies.
immunotherapy
While autophagy inhibition in combination with ERK
inhibition has shown promising results for PDAC Recent studies have demonstrated that both tumor-
patients, other cancers mediated by RAS activation have intrinsic autophagy and host autophagy play essential
also shown sensitivity to this combination therapy role for tumor cells to escape immunosurveillance [67,72].
[136,137,140]. Therefore, it would be worth determining if Moreover, HCQ synergizes with ICB therapy to inhibit
all RAS-driven cancers are susceptible to this therapeutic pancreatic tumor growth [72]. Host autophagy inhibition
modality. Furthermore, studies should be conducted to also promotes inflammation in the tumor microenviron-
determine whether the effectiveness of autophagy inhibi- ment to enhance immune surveillance [67]. A noncanoni-
tion is specific to RAS-driven cancers or whether it can be cal function of the essential autophagy gene FIP200 was
effective for other cancer types as well. found to limit T-cell recruitment in mammary tumors
and promote tumor progression. When combined with
immune checkpoint inhibitors, ablation of FIP200
Autophagy inhibition combined with mTOR
enhanced efficacy of this therapy and slowed tumor
inhibitors
growth [42]. Based on these animal experiments, studies
mTOR regulates cell growth, proliferation, and sur- combining autophagy inhibitors and immune checkpoint
vival via mTORC1 and mTORC2, which are often inhibitors may hold promise for human trials.
Autophagy inhibition combined with other inhibitors. ULK1 inhibitors, such as SBI-0206965, aim
therapies to suppress ULK1’s function in phosphorylating
enzymes required for autophagy initiation [155]. Vps34
Many forms of cancer therapy such as chemotherapy
inhibitors, such as SAR405, aim to inhibit Vps34’s role
and radiotherapy rely on inducing stress in cancer cells
in vesicle trafficking and autophagosome formation
in order to cause tumor death. However, the protective
[156]. Finally, PPT1 inhibitors such as Lys05 aim to
role of autophagy under stress conditions mitigates
deacidify autophagic lysosomes by inhibiting the
these effects and can contribute to therapy resistance.
action of the lysosomal enzyme PPT1 [157].
Autophagy is upregulated in response to many
chemotherapeutic drugs, suggesting that autophagy
inhibition in combination with chemotherapy may yield Identifying potential biomarkers for autophagy
more effective treatments than chemotherapy alone inhibition
[147,148]. Indeed, studies combining autophagy inhibi-
RAS activation promotes tumor cell reliance on autop-
tion with chemotherapy agents have shown promising
hagy [90,158,159]. Studies from preclinical mouse mod-
results [149]. A novel inhibitor of autophagy acting on
els and clinical trials demonstrated autophagy
ULK1 sensitized NSCLC cells to cisplatin and sup-
inhibition could be effective in treating pancreatic can-
pressed cancer cell growth [150]. Promising results have
cer when combined with MEK inhibition or ICB ther-
also been shown in human clinical trials utilizing an
apy [72,136,137]. Similar to PDAC, KRAS mutations
autophagy inhibition and chemotherapy combination
are frequently detected in NSCLC patients and autop-
[149]. A phase Ib/II single-arm study for metastatic
hagy is essential for Kras-driven lung tumor growth
NSCLC utilized carboplatin and paclitaxel chemothera-
[27,28,30]. LKB1, a metabolic sensor and master modu-
pies combined with HCQ. Not only was the treatment
lator of AMPK, is the third most mutated gene
found to be generally safe and tolerable, but patients’
detected in NSCLC. Interestingly, ablation of the
ORR and PFS showed marked improvement [151].
LKB1 causes Kras-driven NSCLC to become much
Radiation therapy often works by inducing DNA
more sensitive to autophagy inhibition compared with
damage in cancer cells, causing them to undergo cell
LKB1 WT lung tumors [30]. Autophagy temporally
death. However, autophagy may serve as a resistance
compensates for acute systemic LKB1 loss for adult
mechanism against this kind of therapy by removing
mouse survival [95]. In the case of Kras-driven lung
damaged DNA and promoting DNA repair, prevent-
tumors, studies suggest that the loss of LKB1 leads to
ing cell death [152]. Therefore, autophagy inhibition
the reduced metabolic plasticity in response to meta-
may also potentiate radiotherapy, and indeed, combin-
bolic stress during tumorigenesis, which is further exag-
ing autophagy inhibitors with radiation has shown
gerated by autophagy ablation, leading to energy crises
improved antitumor effects [149]. Treatment with
in the tumor cell [30]. LKB1 deficiencies are also corre-
chloroquine sensitized bladder cancer cells to radia-
lated with elevated tumor mutational burdens (TMBs)
tion, elevating apoptosis markers, inhibiting prolifera-
in NSCLCs. However, NSCLC patients bearing comu-
tion, and impeding tumorigenesis of xenograft tumors
tations of LKB1 and KRAS are resistant to
[153]. A study on whole-brain radiation therapy com-
immunotherapy [160]. Recent studies found that, com-
bined with chloroquine showed that treatment was
pared to LKB1 WT lung tumors, LKB1-deficient can-
well tolerated and suggested a survival benefit com-
cers treated with autophagy inhibitors show higher
pared with radiotherapy alone [154]. Autophagy inhi-
sensitivity to immune checkpoint blockade anti-PD-1
bition may play role as a treatment modulator even
treatment [73]. As a result, LKB1 mutations could con-
for radiotherapy.
sequently be explored as a predictive biomarker for the
treatment of lung cancers with autophagy inhibition.
However, the potential of LKB1 biomarkers still
Developing new autophagy inhibitors
requires further investigation.
So far, CQ and its derivative HCQ are the only FDA-
approved autophagy inhibitors for clinical usage.
Addressing arguments that autophagy
Indeed, besides blocking the fusion of autophagosomes
is antitumorigenic
with lysosomes using CQ and HCQ, autophagy pro-
cesses can be targeted at multiple steps, leading to While the above studies certainly point to the
other autophagy inhibition strategies that are currently autophagy-mediated tumor promotion and promising
under investigation, including Vps34 inhibitors, ULK1 effects of autophagy inhibition in cancer treatment,
inhibitors, and palmitoyl-protein thioesterase 1 (PPT1) this contention is certainly up for debate. Other studies
report that autophagy can actually be antitumorigenic cells therefore is a fruitless endeavor [167]. However,
and thus oppose inhibiting autophagy in cancer lines extensive data support the importance of tumor-
[126,161,162]. For example, one study has shown that intrinsic autophagy, in addition to host autophagy, in
immunosurveillance against transplanted carcinomas promoting cancer energy homeostasis, metabolism,
can be improved by pharmacologically inducing autop- attenuation of oxidative stress, and immune tolerance
hagy under specific caloric restrictions [163]. The role [29,30,72,73,103–105].
of autophagy in cancer and tumor progression seems
paradoxical due to apparently contradictory effects of
Concluding remarks
autophagy dysfunction. It has been shown that autop-
hagy serves as a survival mechanism for tumor cells in This review seeks to provide a broad overview of the
response to metabolic stress, but there is growing evi- interactions of autophagy and cancer as well as examine
dence for autophagy as a tumor suppression mecha- potential clinical applications of findings in this area.
nism. This evidence includes findings that deletion of Cell-autonomous autophagy supports tumor growth via
essential autophagy genes suppressed tumor initiation intracellular recycling to maintain essential nutrients,
in mouse models of breast cancer and that defects in removing toxicity caused by the accumulation of protein
autophagy resulting from allelic loss of Beclin-1 pro- aggregates and damaged organelles, inhibiting p53 func-
mote tumorigenesis and are commonly observed in tion, and preventing cell surface expression of MHC I
multiple human cancers [126,161]. However, this evi- for antigen presentation to escape immunosurveillance.
dence is complicated by studies that demonstrate that Host autophagy supports tumor growth by sustaining
loss of BECN1 in breast cancer does not occur inde- necessary levels of essential amino acids and metabolites
pendently of deletion of BRCA1, a known tumor sup- for tumor cell metabolism and inhibiting innate and
pressor gene [162,164]. This suggests that BRCA1 is adaptive antitumor immune responses. Given its role in
the main driver or tumorigenesis in these cases [61]. cell metabolism and immune responses, autophagy inhi-
Indeed, core autophagy machinery and genes are gen- bition can potentially be combined with MAPK/ERK
erally not mutated across most cancers [165]. inhibitors, mTOR inhibitors, or immunotherapy as
Another argument against autophagy inhibition is novel cancer therapies. Autophagy and its role in cancer
tolerability. Some studies state that human cancer lines continue to be uncovered, and further research in this
grown in vitro remain unaffected and show no size area can reveal new ways to target various kinds of can-
reduction when Atg genes are deleted [166]. However, cer and disease.
it has been shown that autophagy-ablated tumors
indeed display growth defects and can be restored
Acknowledgments
upon nutrient-rich conditions despite being sensitive to
starvation [28,30]. Additionally, the in vitro environ- This work was supported by supported by NIH grant
ment may lack crucial antitumor effects that are R01CA237347-01A1, ACS grant 134036-RSG-19-165-
prominent within the in vivo environment, such as 01-TBG, the GO2 Foundation for Lung Cancer, Rut-
immune responses, stromal cells in tumor microenvi- gers Busch Biomedical Grant, the New Jersey Health
ronment, or development of resistance mechanisms. Foundation, Rutgers and Princeton Collaboration
Indeed, by claiming to observe tumor reduction in Seed Funding Pilot Award, and Seed Funding for
mice which have compromised immune systems Large Multi-PI Awards to JYG; and NJCCR Pre-
[27,67,72], critics argue that immunocompromised mice doctoral Fellowship Award, Steven A. Cox Founda-
models neglect the realistic activation of the host tion Award, and Mistletoe Research Fellowship to
immune system compared to autochthonous models VB.
[166]. However, the use of nude mice is critical to
investigate tumor progression dependency on onco-
Conflict of interest
genic signaling. Additionally, nude mice do not neces-
sarily neglect in vivo host immune responses, as The authors declare no conflict of interest.
activation of innate and adaptive immune responses is
defining characteristics of autophagy-deficient tumor
Author contributions
cells [64].
An additional argument proposes that it is only host JYG was the leading principal investigator who con-
autophagy that promotes tumor growth, not tumor ceived the structure of the article. JYG, MR, and JK
cell-autonomous autophagy. Proponents of this argu- wrote the article. KK and VB assisted with some edi-
ment conclude that inhibition of autophagy in cancer tion.
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The FEBS Journal - 2021 - Rangel - Autophagy and Tumorigenesis

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STATE-OF-THE-ART REVIEW

Autophagy and tumorigenesis

(Received 14 April 2021, revised 28 June

Fig. 1. Autophagy regulatory pathways. The

Fig. 3. Common functions of autophagy.

Fig. 6. Autophagy in cancer treatment.

References 16 Mathew R, Kongara S, Beaudoin B, Karp CM, Bray

81 Le Texier L, Lineburg KE, Cao B, McDonald-Hyman products in modulating the IGF-1-AKT-mTOR

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