Cellular Self-Digestion Unveiled: Autophagy's Impact on Cancer

Autophagy is a strictly controlled process in which cells break down and recycle their own components by transporting them to lysosomes. Multiple studies have shown that autophagy has a diverse range of physiological and pathological functions in cells. Autophagy in cancer has contradictory functions, serving as both a suppressor and a driver of tumor growth. Specifically, it may exhibit several roles in relation to cancer treatment, either leading to cancer resistance or enhancing susceptibility to radiation and chemotherapy. Hence, autophagy has the potential to augment the efficacy of anticancer medications and radiation treatment.


Introduction
Autophagy is a dynamic cellular process where proteins and organelles are enclosed inside intracellular membrane structures for the purpose of degradation and turnover.This mechanism is evolutionarily conserved and takes place in all eukaryotic cells, ranging from yeast to humans. of autophagic mechanisms as a new strategy for treating cancer.

Autophagy Mechanism
Autophagy is a mechanism that is exceptionally conserved throughout evolution.It helps to fulfil metabolic needs and maintain homeostasis by using an intracellular recycling system or selfdegradation. 9Autophagy is triggered in several cellular stress situations, including hunger, cellular injury, and the accumulation of faulty proteins. 10Autophagy may be categorized into three types: microautophagy, macroautophagy, and chaperone-mediated autophagy (CMA).
Macroautophagy has a role in segregating cytoplasmic cargo into phagophores, leading to the creation of autophagosomes that consist of double membrane vesicles.Subsequently, CBMJ 2024 January: Vol. 13 No. 01 autophagosomes combine with lysosomes to create autolysosomes, which then proceed to perform the processes of degradation and recycling. 11 Microautophagy is a kind of autophagy where cytosolic components are directly engulfed by the lysosomal membrane via the capture of cargo.
12 Chaperone-mediated autophagy is a kind of autophagy that selectively targets specific cargo.
This process involves the recognition and transport of cargo, which is bound to chaperone proteins like HSC70, across the lysosomal lumen.
The transport is facilitated by a receptor on the lysosomal membrane called lysosomalassociated membrane 2A (LAMP-2A) 13 Different autophagic pathways that might be present in cancer cells are described in Fig. 2.
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Macroautophagy
The macroautophagic process involves many distinct stages, including initiation, nucleation, and maturation.During the initial stage, the production of phagopores involves the participation of many autophagy-related genes (ATGs), which are derived from mitochondria, endoplasmic reticula, and plasma membranes.prevents harm to cellular architecture and function. 18The signalling pathways that govern mitophagy may be categorized into the following two groups: PTEN-induced putative kinase 1 (PINK1) Parkin-mediated and non-mediated processes. 16

Chaperone-mediated autophagy
Chaperone-mediated autophagy is a specific kind of autophagy that has distinct mechanisms for identifying and moving cargo into the lysosomal membrane in mammalian cells. 13CMA focuses on proteins that are specifically targeted by heat shock 70 kDa protein 8 (HSC70).HSC70 is

Cancer and Autophagy
Autophagy was first linked to cancer, making it one of the earliest illnesses to be related with this cellular process.

Apoptosis and Autophagy
The question of whether autophagy finally eradicates cancer cells is still a subject of debate.
The observation of autophagic vacuoles in cancer cells undergoing therapy suggests that they experience autophagy-mediated cell death.
However, it is important to note that the relationship between autophagy and cell death is not necessarily a direct cause-and-effect correlation.Anticancer therapies may cause harm to the organelles inside cancer cells, leading to the activation of autophagy as an early response.
Autophagy serves to safeguard the cells by isolating and breaking down the damaged organelles.Nevertheless, when a certain threshold of damage inside cells is surpassed, autophagy may be activated to eliminate the damaged cells from a tissue by the induction of cell death. 37In autophagic cell death, caspases remain inactive and there is no observable DNA degradation or nuclear fragmentation, which may be evaluated using DNA laddering techniques.

Immunotherapy and Autophagy
The significance of immune response in cancer treatment has been increasingly attracting attention.Autophagy has recently been identified as a significant factor in the control of immunological recognition and response.

Cancer Therapy and Autophagy
While autophagy has historically been seen as a system that promotes cell survival and protection,

Fig. 1 .
Fig. 1.Biological process of autophagy (Autophagy may be triggered by conditions such as food deprivation, pathogen invasion, and other environmental stresses.Autophagy begins by sequestering double-membrane-bound components inside a fully intact cell).
autophagocytosis, is responsible for the removal of aging or damaged mitochondria.17 CBMJ 2024 January: Vol. 13 No. 01 Mitochondria that experience impaired function are destroyed via the process of mitophagy.This ensures the generation of new mitochondria and

Fig. 2 .
Fig. 2. Different autophagic pathways present in cancer cells (Macroautophagy is a widely occurring autophagic pathway, mitophagy is a specialized form of autophagy that specifically targets mitochondria, and chaperone-mediated autophagy is a selective form of autophagy with a distinct mechanism.The autophagic route is shown by black arrows.The autophagic signal channel is shown by red arrows).

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Autophagic cell death, in contrast, is distinguished by the breakdown of the Golgi apparatus, polyribosomes, and endoplasmic reticulum prior to nuclear disintegration.These organelles, on the other hand, are conserved in apoptosis.Thus, the presence of caspaseindependent cell death, together with a higher quantity of autophagic vesicles, might potentially serve as a distinguishing characteristic of autophagic cell death. 38-40To accurately identify cells undergoing autophagic death, it is necessary to combine autophagy detection tests with other morphological and biochemical investigations, since there is no straightforward and singular approach available for this purpose.Despite the fact that tumor cells have been seen to experience both apoptosis and autophagic cell death in response to treatment, there is little understanding of the relationship between these two processes. 8Apoptosis and autophagy may exhibit crosstalk, indicating that they are not necessarily distinct processes.Apoptosis is often induced by inhibiting autophagy, whereas inhibiting apoptosis leads to the activation of autophagy. 41,42These data suggest a potential relationship between apoptosis and autophagy.Nevertheless, when tamoxifen was administered to breast cancer cells, electron microscope research revealed that some cells were undergoing apoptosis, others were undergoing autophagy, and others exhibited indications of both processes. 43However, further research is CBMJ 2024 January: Vol. 13 No. 01 required to ascertain the different pathways that may govern the initiation of autophagy by anticancer treatments.

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Research has shown that autophagy enhances the immunogenicity of tumor cells by participating in the processing of tumor antigens and the subsequent activation of effector T-lymphocytes.Hence, implementing techniques that target autophagy induction might be used as an adjunct to enhance the stimulation of the anticancer immune response.For instance, the use of vaccines made from tumor autophagosomes has been shown to stimulate the production of cytotoxic immune cells and, as a result, trigger antitumor responses in mice that have lung carcinoma and melanoma cell lines. 45Recent research indicates that inhibiting autophagy enhances the antitumor immune response in immunotherapeutic approaches, such as T-cell transfer, vaccines, and the administration of antibodies or recombinant cytokines.This is because heightened autophagy levels in cancer cells tend to suppress the antitumor immune response. 46According to published research, blocking autophagy may enhance the ability of activated effector T and NK cells to kill tumor cells.Administering large doses of IL-2 in conjunction with chloroquine resulted in improved long-term survival, reduced toxicity related to vascular leakage, and higher proliferation and infiltration of immune cells in the liver and spleen. 47Autophagy also has a crucial function in enhancing the immunogenicity of tumor cells.It is involved in antigen processing and the subsequent activation of effector T-cells.Inducing autophagy might be used as an additional technique to activate the immune response against tumors.45,48 individuals with myeloma showed a greater incidence of partial response and stable illness.53,55,56While clinical studies have shown the feasibility of inhibiting autophagy in patients with these drugs, there is still scope for further enhancement.Furthermore, these particular drugs, although having previously received approval from the FDA, need to be given at larger doses in order to suppress autophagy and remain in the patients' bodies for extended durations, up to five years.53,57 Alternatively, the stimulation of autophagy may enhance the efficacy of anticancer treatments in cases when autophagy itself is harmful to cells, either by directly causing cell death or by triggering other mechanisms of cell death, such as apoptosis.50,58,59 Various medicines and natural extracts, including those currently used in clinical settings, have been shown to trigger autophagy-mediated cell death in various types of cancer cells.36,60-66 Challenges and Future Directions Research suggests that the regulation of autophagy plays a crucial role in the development of tumors, therefore presenting a potential target for therapeutic intervention.Firstly, in cancer cells with impaired autophagy, which makes them resistant to cell death, introducing autophagyinducing signals such as upregulating or activating BECN1 or PTEN may induce cell death or hinder cell growth.While the introduction of BECN1 into breast cancer cells using stable transfection enhances autophagic activity and decreases tumorigenic ability 67 , there is currently no research documenting the antitumour impact of BECN1 expression in experimentally developed tumours.Secondly, medicines like rapamycin have the potential to trigger autophagic cell death in cancer cells that are already capable of undergoing autophagy.Evaluating the initiation of autophagy in tumor samples collected from patients has aided in determining the tumor cells' ability to undertake autophagy. 68-71Autophagy was seen in 7 out of the 12 tumor types examined using transmission electron microscopy, including breast and lung cancer. 72Although the sample size of tumors was modest, the authors hypothesized that autophagy is present in a wide range of tumors.Thirdly, in tumor cells where the activation of autophagy is responsible for treatment resistance, the use CBMJ 2024 January: Vol. 13 No. 01 of autophagy inhibitors like bafilomycin A1 might enhance the sensitivity of cancer cells to therapeutic drugs by shifting the autophagic process towards an apoptotic phase.Assessing the impact of autophagy inhibitors might be beneficial in determining whether tumor cells rely on autophagy activation for survival during treatment.