Autophagy in tumor immune escape and immunotherapy

Abstract

The immunotherapy targeting tumor immune escape mechanisms has become a critical strategy in anticancer treatment; however, the challenge of immune resistance remains significant. Autophagy, a cellular response to various stressors, involves the degradation of damaged proteins and organelles via lysosomal pathways, maintaining cellular homeostasis. This process not only supports tumor cell survival but also profoundly impacts the efficacy of cancer immunotherapies. The modulation of autophagy in tumor cells or immune cells exerts dual effects on tumor immune escape and immunotherapy. However, the mechanistic details of how autophagy influences the immune system and therapy remain inadequately understood. Given this complexity, a deeper understanding of the role of autophagy in the tumor-immune landscape could reveal novel therapeutic avenues. By manipulating autophagy appropriately, it may be possible to overcome immune resistance and enhance the effectiveness of immunotherapeutic strategies. This article summarizes the role of autophagy in tumor immunity, its relationship with immunotherapy, and the potential therapeutic benefits of targeting autophagy to strengthen antitumor immune responses and optimize the outcomes of immunotherapy.

Keywords: Autophagy; Cancer; Immune escape; Immune resistance; Tumor immune microenvironment.

Fig. 1

The brief process of autophagy. Autophagy is regulated by signaling pathways such as AMPK and mTOR. It involves the assembly of the ULK and VPS34 complexes, which facilitate the formation of double-membrane phagophores that subsequently mature into autophagosomes. These structures then fuse with lysosomes to form autolysosomes, where the contents are degraded, allowing for the recycling of cellular components. (Created in https://BioRender.com)

Fig. 2

Autophagy and Its Regulatory Role in PD-L1 Expression in Tumor Cells. Autophagy plays a crucial regulatory role in the expression of PD-L1 in tumor cells. On one hand, autophagy regulates the translation and transcription of PD-L1, with mediators or drugs such as TPSO, CXCL12, and 5HT1aR, as well as curcumin, influencing this pathway. On the other hand, processes involving the autophagic degradation of PD-L1 are mediated by key factors such as mTORC1, TRIM14, and PPARγ, along with specific drugs (e.g., sunitinib, andrographolide) that regulate this pathway. The interaction between autophagy and PD-L1 expression is essential for understanding the mechanisms of immune evasion in tumors and highlights potential therapeutic interventions targeting these processes. (Created in https://BioRender.com)

Fig. 3

Regulation of Immune Checkpoints MHC-I Expression in Tumor Cells by Autophagy. Most studies have shown that promotion of autophagy downregulates MHC-I expression and suppresses the immune response. Autophagy cargo receptor NBR1 binds MCH-I and recruits it to autophagic vesicles to induce degradation, and this mechanism can be used by HIF1A-AS2, RIPK2, etc. Treatments such as CXCL1 and progranulin can also induce autophagy to reduce the level of MCH-I. However, autophagy regulates MHC-I expression in a bidirectional manner, for example, autophagy induced by radiotherapy can increase MHC-I expression in a dose-dependent manner. (Created in https://BioRender.com)

Fig. 4

Autophagy and its role in immunoregulation in tumor cells through other modalities. Autophagy regulates tumor immunity by modulating the expression of other tumor cell surface molecules, influencing cytokine expression, and regulating metabolite secretion; in addition, a variety of substances can modulate the immune response by influencing autophagy to regulate the release of DAMPs. (Created in https://BioRender.com)

Fig. 5

The Autophagy Occurred in Immune Cells. Autophagy plays a complex role in various immune cells within the tumor microenvironment, including T cells, macrophages, monocytes, DCs, neutrophils, and myeloid-derived suppressor cells MDSCs. For example, ER stress and hydroxyproline inhibit autophagy in monocytes, leading to immunosuppressive effects. Conversely, stimulants like β-glucan and docosahexaenoic acid promote DCs autophagy, resulting in immune activation. This regulation underscores the significant interplay between autophagy and immunity, highlighting potential therapeutic strategies in cancer treatment. (Created in https://BioRender.com)