Autophagy, a fundamental cellular process responsible for cellular component degradation and recycling, has gained considerable importance in the field of cancer research. Initially identified as a tumor suppressive mechanism, the role of autophagy in cancer has proven to be complex, exhibiting both pro-survival and pro-death effects depending on the specific context. This review aims to explore the intricate interplay between autophagy and cancer, shedding light on its diverse implications in tumor development, progression, and response to treatment. A comprehensive understanding of the dynamic nature of autophagy in cancer is crucial for the development of targeted therapeutic strategies that capitalize on autophagy modulation to improve patient outcomes.
Autophagy, a tightly regulated cellular process crucial for cellular homeostasis and stress adaptation, acts as an internal recycling system. It selectively engulfs and transports damaged organelles, protein aggregates, and cellular components to lysosomes for degradation [1, 2]. In the context of cancer, the role of autophagy is multifaceted, exhibiting both tumor-promoting and tumor-suppressive effects contingent on the specific tumor stage and microenvironment. Understanding the intricate relationship between autophagy and cancer is essential for unraveling its diverse implications in tumor progression and response to therapy . In certain contexts, autophagy promotes tumor growth by facilitating the survival of cancer cells under unfavorable conditions such as nutrient deprivation and hypoxia, as well as aiding in immune evasion and therapy resistance . Consequently, targeting autophagy has been explored as a potential therapeutic strategy to hinder cancer progression.
Conversely, autophagy also exhibits tumor suppressor functions. By eliminating damaged organelles and proteins, autophagy preserves genomic stability and prevents the accumulation of harmful cellular components that could trigger tumorigenesis . Furthermore, autophagy can induce cell death in cancer cells, acting as a safeguard against the survival of malignant cells . Defects in autophagy have been associated with increased cancer incidence and poorer patient outcomes, underscoring the significance of autophagy in cancer biology.
The intricate interplay between autophagy, the tumor microenvironment, genetic alterations, and signaling pathways further contribute to the complexity of autophagy’s impact on tumor development and progression. Understanding the context-dependent role of autophagy in cancer is crucial for developing targeted therapeutic interventions and optimizing patient outcomes. This review provides a comprehensive perspective on the dual nature of autophagy in cancer, emphasizing its implications for future research and clinical applications.
Autophagy in Tumor Initiation and Progression: In the early stages of cancer, autophagy serves as a crucial tumor suppressor mechanism by eliminating damaged organelles, reducing genomic instability, and maintaining cellular homeostasis . Impairment of autophagy has been associated with increased accumulation of damaged proteins, genomic instability, and activation of oncogenic signaling pathways . This highlights the importance of intact autophagy in preventing the initiation and progression of cancer. However, as tumors progress and face challenging microenvironments, autophagy can be exploited by cancer cells to promote their survival and growth . Cancer cells upregulate and enhance autophagy as a survival strategy to cope with adverse conditions such as nutrient scarcity, low oxygen levels (hypoxia), and metabolic stress . By utilizing autophagy, cancer cells can break down cellular components and recycle their constituents, thus generating crucial energy and building blocks necessary for their survival and aggressive behavior .
Enhanced autophagy in cancer cells promotes their
adaptation to the hostile tumor microenvironment, enabling
them to overcome nutrient limitations and evade cell death
signals. This autophagy-mediated metabolic rewiring supports
the metabolic demands of rapidly dividing cancer cells, facilitating
their proliferation and invasive properties . Moreover,
autophagy can facilitate the resistance of cancer cells to various
therapies, including chemotherapy and radiation, by aiding in the
removal of damaged molecules caused by these treatments and
promoting cell survival . The interplay between autophagy
and cancer progression is complex and context dependent. While
autophagy initially acts as a protective mechanism, preventing
the accumulation of detrimental cellular components, its
dysregulation can lead to a shift towards pro-tumorigenic effects.
The intricate balance between autophagy’s tumor-suppressive
and tumor-promoting functions is influenced by factors such as
the tumor microenvironment, genetic alterations, and signaling
Autophagy is a key player in the development of resistance
to different anticancer therapies, encompassing chemotherapy,
radiation, and targeted therapies. Cancer cells can exploit
autophagy as a survival mechanism, allowing them to withstand
the stress imposed by these treatments . However, this reliance
on autophagy for therapy resistance also presents an opportunity
for therapeutic intervention.
Autophagy-mediated drug resistance is achieved through
Firstly, autophagy can act as a protective mechanism by
removing damaged molecules and organelles induced by
anticancer treatments. By eliminating these harmful components,
cancer cells can evade therapy-induced cell death pathways and
maintain their survival . Additionally, autophagy enables
cancer cells to adapt to the hostile tumor microenvironment
caused by therapy, such as nutrient deprivation and hypoxia .
By recycling cellular constituents through autophagy, cancer cells
can sustain their energy production and metabolic requirements,
thereby promoting their survival and regrowth .
However, the reliance of cancer cells on autophagy for
therapy resistance also represents a potential vulnerability that
can be targeted. Modulating autophagy in combination with
standard cancer treatments has emerged as a promising strategy
to overcome therapy resistance. Preclinical and clinical studies
have explored approaches to either inhibit or activate autophagy
to sensitize cancer cells to therapy-induced cell death .
Autophagy inhibition can sensitize cancer cells to therapy by
preventing their ability to cope with stress conditions. Inhibiting
autophagy can lead to the accumulation of damaged components
and organelles, overwhelming the cellular defense mechanisms
and ultimately triggering cell death pathways . This approach
has shown efficacy in enhancing the effectiveness of various
On the other hand, autophagy activation can also be exploited
to sensitize cancer cells to therapy. Under certain circumstances,
stimulating autophagy in cancer cells can overwhelm their
adaptive capabilities, making them more susceptible to therapyinduced
cell death through several mechanisms .
Firstly, autophagy activation can lead to the excessive
degradation of cellular components and organelles, including
damaged proteins and dysfunctional organelles. This process
helps to eliminate the building blocks that cancer cells rely on for
survival and growth. By degrading these essential components,
autophagy induction deprives cancer cells of the necessary
resources to maintain their viability, ultimately leading to their
demise . Secondly, autophagy activation can disrupt the
cellular energy balance in cancer cells. Cancer cells require a
substantial amount of energy to support their rapid proliferation
and survival. By activating autophagy, cellular energy stores,
such as glycogen and lipids, can be broken down and utilized as
an energy source. This energy deprivation weakens the adaptive
capabilities of cancer cells, making them more susceptible to the
cytotoxic effects of anticancer therapies .
Moreover, excessive autophagy induction can trigger an
overload of the cellular degradation machinery, overwhelming the
capacity of cancer cells to cope with the stress imposed by therapy.
This overload can lead to the accumulation of toxic autophagic
intermediates and the generation of reactive oxygen species (ROS),
both of which can induce cellular damage and promote cell death
pathways . Additionally, autophagy activation can enhance the
immune response against cancer cells. Autophagy plays a critical
role in antigen presentation and the activation of immune cells.
By inducing autophagy, cancer cells can increase the presentation
of tumor-specific antigens to immune cells, leading to a stronger
immune response against the tumor . This immune-mediated
cytotoxicity can synergize with the effects of anticancer therapies,
further promoting cancer cell death.
It is important to note that the effects of autophagy stimulation
on cancer cell susceptibility to therapy-induced cell death can
vary depending on the specific context, including the tumor
type, genetic alterations, and the microenvironment. Therefore,
a comprehensive understanding of these factors is necessary to
determine the optimal strategies for autophagy modulation in
combination with anticancer therapies. Combining autophagy
activators with conventional treatments has demonstrated
promising results in preclinical models and is being investigated
in clinical trials . It is important to note that the modulation
of autophagy in cancer therapy is a complex endeavor, as the
effects of autophagy modulation can vary depending on the tumor
type, microenvironment, and stage of cancer. Therefore, a deeper
understanding of the molecular mechanisms and context-specific
effects of autophagy modulation is necessary for the development
of effective therapeutic strategies.
The tumor microenvironment significantly influences the role
of autophagy in cancer. Various components, including stromal
cells, immune cells, and extracellular matrix, can modulate
autophagy within the tumor microenvironment. For instance,
autophagy in cancer-associated fibroblasts can promote tumor
growth and metastasis, while autophagy in immune cells can affect
anti-tumor immune responses . Understanding the intricate
interplay between autophagy and the tumor microenvironment
is crucial for deciphering its impact on tumor progression and
The dual role of autophagy in cancer presents an opportunity
for therapeutic interventions. Strategies to manipulate autophagy
in cancer therapy include autophagy inhibitors, which can
sensitize cancer cells to therapy, and autophagy inducers, which
can promote tumor cell death . However, the challenge lies in
identifying specific contexts and patient populations that would
benefit from autophagy modulation, considering the dynamic and
context-dependent nature of autophagy in cancer.
Autophagy has emerged as a complex and contextdependent
process in cancer biology. Its roles in tumor initiation,
progression, therapy resistance, and interaction with the
tumor microenvironment are multifaceted. Harnessing the
therapeutic potential of autophagy modulation requires a deeper
understanding of the precise mechanisms and context-specific
functions of autophagy in different cancer types. Integrating
autophagy-targeted strategies with existing treatment modalities
holds promise for improving patient outcomes in the future. Further,
autophagy plays a critical role in the development of therapy
resistance in cancer. While cancer cells can exploit autophagy as
a survival mechanism, targeting autophagy represents a potential
strategy to overcome resistance and enhance the efficacy of
anticancer treatments. The modulation of autophagy, either
through inhibition or activation, holds promise as an innovative
approach to sensitize cancer cells to therapy-induced cell death.
Additionally, identifying biomarkers that can predict autophagyrelated
responses in tumors may enable personalized treatment
strategies and improve patient outcomes. Further investigation
into the molecular mechanisms and regulation of autophagy in
different cancer types and stages is essential for harnessing its
potential as a therapeutic target and improving patient outcomes.
There is a strong increase in cancer-related treatments in
Germany which can only in part be attributed to facemasks and
lockdowns. Further research is needed to determine whether the
novel coronavirus vaccines might be a factor regarding the rise in
cancers in Germany, or what other factors (e.g. stress due to job
loss, ) could be involved.