International Journal of Inflammation, Cancer and Integrative Therapy
Open Access

Autophagy is a fundamental cellular process that maintains cellular homeostasis by degrading and recycling damaged proteins and organelles. It plays a critical role in cellular survival, metabolism, and immune responses. In cancer, autophagy can have dual roles: it can suppress tumor initiation by preventing the accumulation of damaged cellular components, but it can also promote tumor survival and progression under stressful conditions, such as low nutrient availability or hypoxia. In addition to its role in cellular maintenance, autophagy is intricately linked to inflammation, a key factor in cancer development and progression. Chronic inflammation within the tumor microenvironment (TME) can promote tumor growth, angiogenesis, and metastasis. Given the complex relationship between autophagy and inflammation, targeting autophagy offers a promising strategy to modulate inflammation in cancer therapy. This article explores how autophagy influences inflammation in cancer and how therapeutic modulation of autophagy could enhance cancer treatment by altering inflammatory pathways [1].

Description

Autophagy and inflammation in cancer

Autophagy and inflammation are interconnected processes that influence cancer progression in multiple ways. Inflammation in the TME is driven by the activation of immune cells, cytokines, and other inflammatory mediators that create a microenvironment conducive to tumor growth. This inflammatory milieu can promote tumor cell survival, immune suppression, angiogenesis, and invasion. Autophagy, on the other hand, regulates many aspects of inflammation, such as immune cell activation, cytokine production, and tissue repair, and can either exacerbate or suppress inflammation depending on the context [2].

Autophagy and immune responses: Autophagy is involved in the regulation of innate and adaptive immune responses. In immune cells such as macrophages, dendritic cells, and T lymphocytes, autophagy plays a critical role in antigen presentation, cytokine production, and immune cell activation. In cancer, autophagy can modulate the inflammatory response by regulating the function of these immune cells. For instance, autophagy in macrophages can determine whether they adopt a pro-inflammatory (M1) or anti-inflammatory (M2) phenotype. The M1 macrophage phenotype promotes anti-tumor immunity, while the M2 macrophage phenotype supports tumor growth and immune evasion.

Autophagy and cytokine regulation: Autophagy also regulates the release of inflammatory cytokines such as IL-6, TNF-α, and IL-1β, which are commonly elevated in cancer and contribute to the chronic inflammation observed in the TME. In some cases, autophagy can limit inflammation by suppressing the activation of pro-inflammatory signaling pathways such as NF-κB, while in other cases, it can enhance inflammation by facilitating the activation of inflammasomes or promoting the secretion of cytokines that favor tumor growth.

Autophagy in tumor cells: In cancer cells, autophagy is often upregulated to support tumor survival and adaptation to stressors such as nutrient deprivation, hypoxia, and therapeutic treatment. Autophagy helps tumor cells survive by recycling cellular components, allowing them to maintain energy homeostasis and avoid cell death. However, the increased autophagic flux in cancer cells can also promote the release of damage-associated molecular patterns (DAMPs) and inflammatory cytokines into the TME, exacerbating inflammation and creating a vicious cycle that enhances tumor progression [3].

Autophagy and tumor-associated inflammation: Tumor-associated inflammation can also impact autophagy, creating a feedback loop between these two processes. For example, inflammatory cytokines such as IL-1β and TNF-α can activate autophagy in tumor cells, which, in turn, enhances the production of pro-inflammatory molecules and promotes tumor growth. On the other hand, autophagy inhibition in the TME can reduce inflammation and promote anti-tumor immunity by reversing the immunosuppressive environment created by inflammatory cells [4].

Targeting autophagy to modulate inflammation in cancer therapy

Given the complex role of autophagy in inflammation and cancer, targeting autophagy as a therapeutic strategy offers a way to manipulate the inflammatory microenvironment and improve cancer treatment outcomes. The goal is to either inhibit autophagy to prevent tumor cells from adapting to stress and reducing inflammation, or to activate autophagy to enhance immune responses and promote anti-tumor immunity. Several approaches have been developed to target autophagy in cancer therapy, including the use of autophagy inhibitors, autophagy activators, and combination therapies that synergize with other cancer treatments [5].

Autophagy inhibitors: Inhibiting autophagy can be an effective strategy to promote tumor cell death and reduce inflammation. Several autophagy inhibitors, such as chloroquine (CQ), hydroxychloroquine (HCQ), and bafilomycin A1, have been tested in clinical trials for their ability to block autophagic flux in cancer cells. By inhibiting autophagy, these drugs can sensitize tumors to chemotherapy, radiation therapy, and immune checkpoint inhibitors. Additionally, autophagy inhibition can reduce the production of inflammatory cytokines in the TME, thereby limiting the pro-tumor inflammation that facilitates cancer progression. For instance, chloroquine has been shown to reduce tumor-associated macrophage infiltration and the secretion of pro-inflammatory cytokines, leading to reduced tumor growth and enhanced anti-tumor immune responses [6].

Autophagy activators: On the other hand, activating autophagy can enhance anti-tumor immunity by promoting immune cell function and improving the presentation of tumor antigens. Several autophagy activators, such as spermidine and resveratrol, have shown promise in preclinical studies for their ability to increase autophagic activity and promote the maturation of dendritic cells, which are key players in initiating immune responses against tumors [7]. Autophagy activation in macrophages can also promote their polarization into the M1 phenotype, which enhances anti-tumor immunity and reduces immunosuppressive effects in the TME. Furthermore, activating autophagy in tumor cells can help boost the efficacy of immunotherapy by enhancing the presentation of tumor-associated antigens and improving the response of immune cells.

Combination therapies: Combining autophagy modulation with other cancer treatments represents a promising approach to improve therapeutic outcomes. For example, combining autophagy inhibitors with chemotherapy can overcome resistance mechanisms by preventing cancer cells from using autophagy to survive treatment-induced stress. Autophagy inhibitors can also enhance the effectiveness of immune checkpoint inhibitors by reducing the immunosuppressive TME and increasing tumor antigen exposure. On the other hand, combining autophagy activators with immunotherapy can enhance the anti-tumor immune response by boosting immune cell activity and cytokine production.

Targeting specific autophagic pathways: Recent advances have also focused on targeting specific components of the autophagic machinery to modulate inflammation in cancer. For example, inhibiting the autophagy-related proteins ATG5 and Beclin-1, which are essential for autophagic vesicle formation, has been shown to reduce inflammation and suppress tumor growth. Additionally, targeting the mTOR pathway, a key regulator of autophagy, can either inhibit or activate autophagy, depending on the therapeutic goals. mTOR inhibitors, such as rapamycin, can suppress autophagy and reduce inflammation, while mTOR activators can enhance immune responses and improve anti-tumor immunity [8].

Conclusion

Autophagy plays a critical role in both cellular homeostasis and inflammation, two processes that are intricately linked to cancer development and progression. In the tumor microenvironment, autophagy can either exacerbate or suppress inflammation depending on the context, influencing tumor growth, metastasis, and response to therapy. Targeting autophagy presents a promising strategy to modulate inflammation in cancer therapy, with the potential to either inhibit autophagy to sensitize tumors to treatment or activate autophagy to enhance immune responses. Autophagy inhibitors, activators, and combination therapies are currently being explored in preclinical and clinical settings, offering new opportunities for improving cancer treatment outcomes. As our understanding of the molecular mechanisms underlying autophagy and inflammation deepens, the development of more precise autophagy-targeted therapies will be essential for advancing cancer therapy and overcoming therapeutic resistance.

Acknowledgement

None

Conflict of Interest

None

References

1. Moretta L, Bottino C, Pende D, Mingari MC, Biassoni R, et al. (2002) Human natural killer cells: their origin, receptors and function. Eur J Immunol 32: 1205-1211.

Indexed at, Google Scholar, Crossref

2. Vivier E (2006) What is natural in natural killer cells?. Immunol letters 107: 1-7.

Indexed at, Google Scholar, Crossref

3. Paust S, Von Andrian UH (2011) Natural killer cell memory. Nat immunol 12: 500-508.

Indexed at, Google Scholar, Crossref

4. Middleton D, Curran M, Maxwell L (2002) Natural killer cells and their receptors. Transpl immunol 10: 147-164.

Indexed at, Google Scholar, Crossref

5. Geiger TL, Sun JC (2016) Development and maturation of natural killer cells. Curr opin immunol 39: 82-89.

Indexed at, Google Scholar, Crossref

6. Bezman NA, Kim CC, Sun JC, Min-Oo G, Hendricks DW, et al. (2012) Molecular definition of the identity and activation of natural killer cells. Nat immunol 13: 1000-1009.

Indexed at, Google Scholar, Crossref

7. Björkström NK, Strunz B, Ljunggren HG (2022) Natural killer cells in antiviral immunity. Nat Rev Immunol 22: 112-123.

Indexed at, Google Scholar, Crossref

8. Stojanovic A, Cerwenka A (2011) Natural killer cells and solid tumors. J Innate Immun 3: 355-364.

Indexed at, Google Scholar, Crossref