] This review discusses
the involvement of autophagy in tumor immunity and
its importance for cancer therapy. First, we provide a comprehensive overview of the molecular processes
involved in autophagy and the factors that regulate its
function. Next, we consider the intricate relationship
among autophagy, cancer cells, and the immune system,
including the influence of autophagy on evading
the immune response, inflammation associated with
tumors, and the tumor microenvironment (TME).
Eventually, we discuss possible therapeutic approaches
for focusing on autophagy in cancer treatment, as well
as the challenges and future opportunities in this field.
Activation and Regulation of Autophagy
Autophagy is one of the most precisely regulated processes
within the cell, initiated by activation of ULK1
complex. This complex is made up of ULK1, Atg13,
FIP200, and Atg101. The mechanistic target of rapamycin
(mTOR) complex 1 (mTORC1) strictly controls this
complex. mTORC1 is one of the main regulators of cell
metabolism and proliferation. It suppresses autophagy
when nutrients are abundant.[] Whenever the body
receives different stress signals, such as lack of nutrients,
low oxygen levels, or damaged organelles, mTORC1 becomes
inactivated. This deactivation leads to the activation
of the ULK1 complex, which then initiates the autophagy process.[] The initiation of autophagosome
membrane formation is facilitated by the class III phosphatidyl
3-kinase (PI3K) complex, including Vps34,
Vps15, Beclin 1, and Atg14L. The formation of this complex
structure begins with the production of phosphatidyl
3-phosphate (PI3P), which recruits PI3P-binding
proteins to the autophagosome membrane, promoting
its expansion.[] Atg12-Atg5-Atg16L1 and LC3-II (the
lipidated form of microtubule-associated protein 1 light
chain 3, or MAP1LC3) are two ubiquitin-like conjugation
systems that perform the elongation and closing of
the autophagosome membrane. Autophagy receptors,
i.e., p62/SQSTM1, identify ubiquitinated proteins or
damaged organelles, bind to them, and attach them to
LC3-II on the autophagosome membrane, enabling the
sequestration of the cargo.[] (Fig. 1). Subsequently, the
autophagosome and lysosome join together to make an
autolysosome. Lysosomal hydrolases break down the
contents of the autolysosome, and they are then recycled
back into the cytoplasm. These three proteins?the
HOPS tethering complex, the GTPase Rab7, and the
soluble N-ethylmaleimide-sensitive factor attachment
protein receptors (SNAREs)‾are very critical to making
this process feasible. A myriad of signaling path-ways, including mTORC1, AMP-activated protein kinase
(AMPK), and p53 pathways, react to cellular stress
and energy levels to control autophagy. In addition, the
PI3K/Akt pathway, which is an extrinsic signal-regulated
kinase, as well as the cellular ERK and JNK pathways,
which help cells stay alive and grow, are also involved in
controlling autophagy.[] The interplay between these
pathways integrates several signals to precisely modulate
the autophagic response and customize it according
to intracellular requirements and extracellular factors.
Fig. 1. Molecular mechanisms of autophagy.
mTORC1: The mechanistic target of rapamycin complex 1; ATGs: Autophagy-related genes;
FIP200: Focal adhesion kinase family interacting protein of 200 kD; ULK1: UNC-51-like kinase 1;
Vps: Vacuolar protein sorting; PI3Ks: Class 3 phosphoinositide 3-kinases; P62/SQSTM1: Protein
Sequestosome 1; ILC3: Microtubule-associated protein 1A/1B-light chain 3; ILC3-II: ILC3- phosphatidylethanolamine
conjugate.
Regulation of Autophagy by Oncogenes and
Tumor Suppressors
Autophagy is regulated by a complex network of signaling
pathways that respond to many cellular and
environmental signals, including nutrition availability,
energy levels, and stress signals. Oncogenes and
tumor suppressor genes significantly influence numerous
pathways involved in the initiation and advancement
of cancer.[] One example is the oncogene
KRAS, which is commonly mutated in human malignancies.
Studies have demonstrated that KRAS promotes
autophagy by activating the RAF/MEK/ERK
signaling cascade and blocking the mTOR pathway.
This ultimately enables cancer cells to survive and
thrive in stressful settings.[] Conversely, the tumor
suppressor gene PTEN, which is frequently inactivated
or deleted in cancer, inhibits autophagy by enhancing
the PI3K/AKT/mTOR signaling pathway, thereby
resulting in improved cell proliferation and survival.
[] Understanding the molecular pathways through
which oncogenes and tumor suppressors can control
autophagy is essential for the creation of novel therapeutic
strategies that target autophagy in cancer. By
targeting the specific signaling pathways that regulate
autophagy, and tailoring these interventions based on
the unique genetic and molecular profiles of individual
tumors, it may be possible to improve the precision
and efficacy of autophagy-based therapies. This would
allow for better management of cancer treatment and
potentially reduce the risk of resistance and relapse.
Autophagy in Tumor Immunity
The relationship between autophagy and immunity is
complicated. Depending on the stage of the disease,
the type of cancer, and genetic factors, autophagy can
either facilitate or inhibit the progression of the disease.
This section explores the numerous functions of
autophagy in tumor immunity, focusing particularly
on its impact on immune evasion, tumor-associated
inflammation, and TME.
Autophagy and Function of Immune Cells
Autophagy plays a vital role in the functioning and balance
of different types of immune cells, such as T cells,
B cells, NK cells, DCs, and macrophages. It achieves this
by controlling their activation, differentiation, survival,
and effectiveness.[] Autophagy plays a pivotal role in
maintaining T cell silence and preventing autoimmunity.
It achieves this by eliminating damaged mitochondria
and other cellular components, as well as regulating
the expression of important molecules involved in
T cell receptor (TCR) signaling and activation, such as
CD3ζ and Linker for activation of T cells (LAT).[]
Furthermore, autophagy has been associated with the
control of antigen presentation and cross-presentation
by DCs and macrophages. It accomplishes this by aiding
the processing and presentation of antigens on MHC
class I and II molecules, as well as the release of proinflammatory
cytokines like IL-1β and IL-18. These cytokines
can enhance the activation of T cells and other
components of the immune system. Furthermore, autophagy
can regulate the cytotoxic activity of NK cells
by controlling the expression of activating receptors
like NKG2D and the release of cytotoxic granules such
as perforin and granzymes. These granules are critical
to the destruction of target cells.[]
Autophagy and immune evasion
Tumor cells employ various strategies to evade the
immune system, including reducing the expression
of major histocompatibility complex (MHC) class I
molecules, activating immunological checkpoint molecules,
secretion of cytokines that weaken the immune
system, and induction of regulatory T cells (Tregs).[]
Autophagy plays a role in several aspects of immune
evasion, mostly by directly altering the process of presenting
and recognizing antigens, as well as by affecting
the function and fate of immune cells. Autophagy can
promote the presentation of tumor antigens through
MHC class I molecules, facilitating the identification
and eradication of tumor cells by cytotoxic T lymphocytes
(CTLs). Nevertheless, autophagy can inhibit the
process of presenting antigens through MHC class II
molecules, thus enhancing immune evasion and supporting
the growth of tumors.[] Further, autophagy
can augment the production of immunological checkpoint
molecules, like programmed cell death 1 (PD-1)
and its ligand (PD-L1). These molecules restrict the
activation and effectiveness of T cells, thereby contributing
to the development of an immunosuppressive
TME.[] Autophagy can also regulate the activity and
fate of immune cells within the TME. Autophagy, for example, controls the survival, development, and immunosuppressive
function of Tregs, which can weaken
anti-tumor immune responses and facilitate tumor advancement.[] Moreover, autophagy can facilitate the
polarization of tumor-associated macrophages (TAMs)
into an M2-like, anti-inflammatory phenotype, thereby
promoting tumor development and metastasis. Conversely,
autophagy can improve the cytotoxic efficacy
of natural killer (NK) cells and CTLs, enabling them to
eliminate cancer cells.[]
Autophagy and Cancer Stem Cells
Cancer stem cells (CSCs) are a distinct group of cells
inside a tumor that are able to renew themselves
and differentiate into other cell types. These cells
are thought to contribute to the initiation, growth,
metastasis, and resistance to treatment of tumors.
[] Recent evidence indicates that autophagy plays
an important role in the maintenance and functioning
of CSCs, as well as their capability to adapt to
stressful conditions such as hypoxia, food restriction,
and chemotherapy.[] Autophagy has been
demonstrated to enhance the viability and stem celllike
characteristics of CSCs in many forms of cancer,
such as glioblastoma, breast cancer, and colorectal
cancer. This is accomplished through the regulation
of key signaling pathways, including Wnt/β-catenin,
Notch, and Hedgehog.[] Additionally, inhibiting
autophagy has been observed to impair the ability of
CSCs to self-renew, develop tumors, and withstand
chemotherapy in experimental models. This suggests
that targeting autophagy may be a novel approach to
eliminating CSCs and enhancing the effectiveness of
cancer treatment.[]
Autophagy and Tumor Microenvironment
Tumor Microenvironment (TME) comprises a complex
and dynamic system of cellular and non-cellular
constituents, including cancer cells, immune cells,
fibroblasts, endothelial cells, extracellular matrix,
and soluble molecules such as cytokines and growth
factors. The TME plays a key role in cancer progression
and therapeutic responses by influencing various
biological processes, including proliferation, migration,
angiogenesis, and immune evasion.[] Recent
studies have highlighted the importance of autophagy
in the relationship between cancer cells and the
TME, as well as in the ability of cancer cells to adapt
to the fluctuating conditions within the TME, such
as low oxygen levels, acidic pH, and a lack of nutrients.[] For example, autophagy has been shown to assist in tumor angiogenesis by stimulating the release
of pro-angiogenic substances like vascular endothelial
growth factor (VEGF) and by maintaining
the functionality of endothelial cells under stressful
conditions.[] Moreover, autophagy plays a role in
regulating the interaction between cancer cells and
immune cells in the TME, thereby influencing the immune
response to malignancies. Autophagy has been
found to improve the immunosuppressive capabilities
of TAMs and myeloid-derived suppressor cells,
as well as impair the cytotoxic function of NK cells
and CD8+ T cells.[] Metastasis, the spread of cancer
cells from the primary tumor to distant organs, is
the primary cause of cancer-related fatalities. Recent
findings indicate that autophagy plays a crucial role
in regulating metastasis by influencing several cellular
processes, including epithelial-to-mesenchymal
transition (EMT), cell migration, invasion, and resistance
to anoikis.[] Autophagy has been shown to
promote EMT and invasion in breast cancer cells by
degrading E-cadherin, an important regulator of cellcell
adhesion, and by activating focal adhesion kinase
(FAK) signaling.[] Furthermore, the suppression of
autophagy has been observed to inhibit the ability of
cancer cells to spread to other parts of the body in
experimental models, highlighting the potential of
targeting autophagy as a promising strategy for preventing
and treating metastatic disease.[]
Autophagy and Cancer-related Inflammation
Chronic inflammation plays a critical role in the initiation
and progression of various cancers by facilitating
DNA damage, genomic instability, angiogenesis,
and immune evasion. Recent studies have highlighted
the important role of autophagy in controlling inflammation
and its impact on cancer. Autophagy has
been found to regulate the activation of the inflammasome,
a complex of several proteins involved in
the innate immune response, thereby regulating the
production and secretion of pro-inflammatory cytokines,
especially interleukin-1β (IL-1β) and IL-18.
[] Other studies have demonstrated that autophagy
affects the polarization and activity of TAMs, which
have a prominent effect on defining the inflammatory
TME and facilitating the progress of cancer.[]
Therefore, understanding the interplay between autophagy
and inflammation may provide new insights
into the mechanisms underlying cancer development
and identify potential targets for therapeutic intervention.
Tumor-associated inflammation is a determining
factor in the development and progression of cancer. It can increase the growth, survival, blood
vessel formation, invasion, and spread of tumor cells.
[] Autophagy plays a key role in the regulation of
inflammation and the interaction between tumor
cells and immune cells in the TME. Autophagy is
able to regulate the activation of the inflammasome,
a complex of multiple proteins that detect cellular
stress and damage and trigger inflammatory responses.
It impacts the production of pro-inflammatory cytokines,
such as interleukin (IL)-1β, IL-6, and tumor
necrosis factor-alpha (TNF)-α.[] Besides, autophagy
can impact the balance between pro-inflammatory
and anti-inflammatory cytokines and modulate
the polarization and functionality of immune cells
inside the TME, including macrophages, dendritic
cells (DCs), and T cells. Autophagy also controls the
release of different growth factors, chemokines, and
matrix metalloproteinases (MMPs) by both tumor
cells and stromal cells. This process affects the recruitment,
activation, and function of immune cells,
as well as the restructuring of the extracellular matrix
and the development of blood vessels. Consequently,
autophagy contributes to the establishment of a tumor-
supportive microenvironment.[]
Autophagy and Therapy-induced Stress
Throughout the treatment process, cancer cells may
encounter many stressors, including DNA damage,
stress, and the buildup of unfolded proteins. These
stressors might trigger the activation of autophagy as
a mechanism for cell survival.[] Chemotherapy and
radiation are known to induce DNA double-strand
breaks, which activate the DNA damage response
(DDR). This leads to the expression of key ATGs, including
ATG5 and Beclin 1 (BECN1), facilitating the
autophagic process.[] Likewise, specific treatments
that inhibit cancer-causing signaling pathways, such
as BRAF, EGFR, and HER2, can stimulate autophagy
by causing cellular stress and triggering adaptive
feedback mechanisms, which consequently, may lead
to the development of drug resistance.[] To enhance
treatment efficacy and overcome resistance,
targeting autophagy may be a promising strategy. By
inducing cancer cell death or modifying the cellular
stress response, autophagy modulation may sensitize
cancer cells to therapy. However, careful timing
is essential when manipulating autophagy, especially
when combining autophagy inhibitors or activators
with other treatments, to avoid unintended effects
and maximize therapeutic benefits.[]
Targeting Autophagy for Cancer Immunotherapy
Owing to the intricate and situation-specific involvement
of autophagy in tumor immunity, targeting
autophagy may be a promising approach for cancer
treatment. Autophagy can be modulated using pharmacological
drugs, genetic manipulation, or a combination
of both. Here we focus on examining prospective
therapeutic approaches to specifically target
autophagy in cancer treatment, along with the associated
challenges and future approaches in this field.
Cancer immunotherapy, a therapeutic approach that
utilizes the immune system's capabilities to combat
cancer, has demonstrated promising outcomes, especially
through the utilization of immune checkpoint
inhibitors and T-cell therapy. However, many patients
fail to respond or develop resistance to these treatments,
highlighting the need for identifying new targets
and strategies to improve their effectiveness. A
growing area of research explores the relationship between
autophagy and the immune system, as autophagy
has been shown to impact several aspects of tumor
immunity, including antigen presentation, T cell activation,
and cytokine production.[] The combination
of autophagy and immunotherapy offers a promising
strategy to improve immune responses against tumors
and overcome resistance to current therapies.
Recently advances in the development of small
chemicals and biologic elements can control autophagy
in cancer cells. These advancements involve
strategies such as inhibiting autophagosome formation,
obstructing the availability of autophagic energy
sources, or targeting the signaling pathways that regulate
autophagy. Several medicines, including HCQ and
its derivatives, have been tested in clinical studies in
combination with chemotherapy, targeted treatment,
or immunotherapy. These trials have demonstrated
promising results in terms of the rate of response and
progression-free survival.[] However, the effectiveness
of autophagy-targeting agents in treating diseases
may be insufficient due to various factors. These factors
consist of the diverse expression and function of ATGs
in different types of cancer, the activation of alternative
survival pathways, and the potential unwanted effects
on healthy tissues.[] To address these issues, researchers
are focusing on identifying more specific and
potent autophagy inhibitors and developing biomarkers
and predictive tools that can help select the right
patients for treatment and better manage therapeutic
strategies. Moreover, combining autophagy modulation
with other treatment strategies, such as metabolic
reprogramming, immune checkpoint inhibition, or senescence induction, holds the potential for synergistic
anti-tumor effects. This combination approach might
result in enhanced clinical outcomes by overcoming
resistance mechanisms and boosting the immune response
to tumors.[] Several preclinical studies have
demonstrated that combining autophagy targeting
with cancer immunotherapy, e.g., immune checkpoint
blockage, adoptive T cell transfer, or cancer vaccines,
might improve the immune response against tumors
and improve therapeutic effectiveness.[] Blocking
autophagy using HCQ or removing ATGs like Atg5 or
Atg7 has been demonstrated to enhance the effectiveness
of anti-PD-1 or anti-CTLA-4 therapy in various
mouse models of cancer. This combination therapy
works by promoting T-cell activation, increasing T-cell
infiltration into the tumor, and reducing the expression
of immunosuppressive factors in TME.[]
Pharmacological Modulation of Autophagy
A variety of pharmaceutical compounds have been
developed to regulate autophagy by either limiting the
creation of autophagosomes, blocking the fusion of autophagosomes
with lysosomes, or interfering with the
breakdown of autophagic cargo. Certain compounds,
such as chloroquine (CQ) and hydroxychloroquine
(HCQ), have already received approval for treating
other diseases. CQ is utilized as an antimalarial medicine,
whereas HCQ is an anti-inflammatory drug.
These agents have been repurposed for cancer therapy.
[] CQ and HCQ function as lysosomotropic drugs
by accumulating in lysosomes and raising their pH levels.
This disrupts the activity of lysosomal hydrolases
and prohibits the breakdown of autophagic cargo.[]
These medications have been examined alongside different
chemotherapy agents, targeted treatments, and
immunotherapies in both preclinical and clinical investigations.
The findings have been promising, indicating
improved effectiveness against tumors and the ability
to overcome therapeutic resistance.[] However, the
most effective dose, schedule, and indicators for selecting
patients, along with the possible adverse effects and
toxicities associated with prolonged autophagy suppression,
remain unclear.[]
Another pharmaceutical compound targeting autophagy
is 3-methyladenine (3-MA), which inhibits
the class III PI3K complex and blocks the development
of autophagosomes. Bafilomycin A1 is a substance that
inhibits the activity of vacuolar-type H+-ATPase (VATPase),
thereby preventing the acidification of lysosomes
and the breakdown of the autophagic cargo.[]
These agents have primarily been utilized as research instruments for investigating the involvement of autophagy
in cancer and other diseases. Nonetheless,
their therapeutic potential and safety profiles warrant
further investigation. Furthermore, other compounds
that promote autophagy have been explored for their
potential in cancer treatment, either as standalone
therapies or in combination with other therapeutic
approaches. Rapamycin and its analogs, known as rapalogs,
are agents that hinder mTORC1 and stimulate
autophagy.[] Metformin, a medication used to treat
diabetes mellitus, stimulates AMPK and suppresses
mTORC1, resulting in the activation of autophagy
and the manifestation of anti-proliferative properties.
Furthermore, it exhibits anti-inflammatory properties,
specifically targeting tumor cells and cells of the
immune system. Additional autophagy stimulants, including
spermidine, resveratrol, and curcumin, have
demonstrated anticancer and immunomodulatory
properties in preliminary laboratory investigations.
However, their effectiveness and safety in clinical settings
require further evaluation.[]
Genetic Manipulation of Autophagy
Genetic manipulation of autophagy, achieved by either
the overexpression or destruction of specific autophagy-
related genes (ATGs), has been served as a method
to investigate the function of autophagy in tumor immunity
and therapy and develop new therapeutic methods.
For instance, overexpressing Beclin 1 or disrupting
Bcl-2, a protein that inhibits Beclin 1 and autophagy,
has been shown to enhance autophagy and increase the
sensitivity of tumor cells to chemotherapy and radiotherapy
in preclinical models. On the other hand, the
elimination of pivotal ATGs, such as Atg5, Atg7, or
Atg12, has been utilized to impair autophagy and investigate
its impact on tumor development, metastasis,
and immune response in various cancer models.[]
Research has shown that inhibiting the genetic process
of autophagy can decrease tumor growth and improve
the effectiveness of immunotherapy. This provides
strong support for considering the targeting of autophagy
in combination with immune checkpoint inhibitors
or adoptive T-cell treatment.[] The development of
gene therapy techniques, such as the delivery of ATGs
or small interfering RNAs (siRNAs) targeting ATGs via
viral or non-viral vectors, holds significant promise for
modulating autophagy in tumor cells or immune cells,
thereby enhancing the effectiveness of cancer treatments.[] Nevertheless, it is crucial to further optimize
and validate these methods in preclinical and clinical
trials to ensure their efficacy, precision, and safety.
Challenges and Future Directions
Although there is increasing evidence suggesting the
involvement of autophagy in immunity and tumor
therapy, numerous challenges and unresolved challenges
persist. A more comprehensive understanding
of the complex and context-dependent nature of autophagy
is essential. This process can either promote
tumor growth or inhibit it, depending on the illness
stage, cancer type, and unique genetic and environmental
factors. Furthermore, there is a need for more
precise targeting of this mechanism in the context of
cancer treatment. Additionally, for autophagy-targeting
strategies to be successfully applied in clinical settings,
there must be progress in developing more precise and
effective autophagy modulators, along with the identification
of reliable biomarkers for patient selection and
treatment response monitoring. Finally, it is necessary
to investigate the interaction between autophagy and
many cellular processes, including apoptosis, senescence,
and metabolism. Furthermore, understanding
how autophagy communicates with the immune system
is key to elucidating the mechanisms that underlie
the differing effects of autophagy modulation on tumors.
Immune cells are being utilized to develop more
efficient and less harmful therapeutic approaches.
Understanding the Complications of Autophagy
in Cancer
Autophagy is a highly dynamic and context-dependent
process that plays a significant role in cancer. Studies have
demonstrated that the presence of specific elements, such
as the type of cancer, stage, and genetic background, can
result in the manifestation of anti-tumorogenic and antitumor
properties. As a result, a comprehensive understanding
of how autophagy impacts cancer progression
is essential for developing effective treatment strategies.
Researchers are currently focusing on creating advanced
experimental models and technologies, such as genetically
engineered mouse models, organoids, and singlecell
sequencing, to more accurately reflect the complex
nature of human tumors and their surrounding TME.
To make sense of the vast amounts of data generated
by these studies, systems biology approaches, including
computational modeling and network analysis, are being
used to integrate and analyze the information. The goal is
to identify critical regulatory nodes and pathways related
to autophagy and cancer.[]
Development of Autophagy Modulators
The identification and validation of autophagy modulators
with greater specificity and potency are vital for successfully translating autophagy-targeting
strategies into clinical practice. So far, several small
molecules, such as CQ and HCQ, have been used
to inhibit autophagy in preclinical and clinical studies.
Nevertheless, these agents have limitations,
such as poor selectivity, off-target effects, and the
development of resistance. It is crucial to identify
and confirm autophagy modulators that have more
specificity and potency in order to effectively implement
autophagy-targeting approaches in a clinical
setting. To date, numerous small compounds, such
as CQ and HCQ, have been applied to suppress autophagy
in preclinical and clinical investigations.
However, these agents have limitations such as inadequate
selectivity, off-target effects, and the emergence
of resistance.[]
Identifying Biomarkers for Patient Selection
and Monitoring
A major challenge in autophagy-targeting therapy
is identifying patients who are most likely to benefit
from these treatments, as well as monitoring their response
and potential adverse effects. To address this
issue, researchers are actively exploring reliable and
non-invasive biomarkers, such as circulating tumor
cells, cell-free DNA, or extracellular vesicles. These
biomarkers have the potential to accurately predict
the response to autophagy modulators and assist in
the selection of patients for clinical trials and personalized
medicine.[] Moreover, the progress in the
field of imaging methods and tools, such as positron
emission tomography (PET) and magnetic resonance
imaging (MRI), which are able to observe and measure
autophagy in living organisms, will be crucial to
evaluating the effectiveness of treatments and improving
the dosage and timing in clinical research.[]
Interplay between Autophagy and Other
Cellular Processes
Autophagy contributes to other biological processes,
including apoptosis, aging, and metabolism. A
deeper understanding of these processes and their
influence on the dissemination of cancer and the efficacy
of treatment is crucial for the advancement of
more potent therapeutic approaches. One example
of this is the relationship between apoptosis and autophagy,
which are two primary processes involved
in cell death. This interaction is particularly prominent
in the context of cancer, as numerous anticancer
treatments depend on initiation of apoptosis to
eradicate tumor cells. Recent research demonstrates that autophagy can either promote or inhibit apoptosis.
Concomitantly targeting both processes may
enhance the effectiveness of therapy and overcome
resistance to treatment.[]
Autophagy Modulation as an Adjuvant Therapy
Owing to the intricate and diverse nature of autophagy's
involvement in cancer, it is probable that solely
focusing on autophagy may not be sufficient to produce
substantial therapeutic outcomes, especially in
advanced and aggressive cancers. However, regulating
autophagy could serve as an adjunctive strategy
to improve the efficacy of existing treatments and
overcome resistance to therapies, including chemotherapy,
targeted therapy, and immunotherapy.
[38] Numerous preclinical and clinical studies have
shown that inhibiting autophagy can increase the
susceptibility of cancer cells to various anti-cancer
drugs, including temozolomide, cisplatin, and BRAF
inhibitors. This is achieved by promoting cell death,
suppressing survival pathways, and preventing the
development of resistance mechanisms.[] Additionally,
activating autophagy may offer a protective
effect for healthy tissues against the damaging side effects
of radiation and chemotherapy, potentially improving
the therapeutic index and increasing patient
tolerance to these treatments.[]
