Regulation of autophagy fires up the cold tumor microenvironment to improve cancer immunotherapy

Abstract

Immunotherapies, such as immune checkpoint inhibitors (ICIs) and chimeric antigen receptor (CAR) T cells, have revolutionized the treatment of patients with advanced and metastatic tumors resistant to traditional therapies. However, the immunosuppressed tumor microenvironment (TME) results in a weak response to immunotherapy. Therefore, to realize the full potential of immunotherapy and obstacle barriers, it is essential to explore how to convert cold TME to hot TME. Autophagy is a crucial cellular process that preserves cellular stability in the cellular components of the TME, contributing to the characterization of the immunosuppressive TME. Targeted autophagy ignites immunosuppressive TME by influencing antigen release, antigen presentation, antigen recognition, and immune cell trafficking, thereby enhancing the effectiveness of cancer immunotherapy and overcoming resistance to immunotherapy. In this review, we summarize the characteristics and components of TME, explore the mechanisms and functions of autophagy in the characterization and regulation of TME, and discuss autophagy-based therapies as adjuvant enhancers of immunotherapy to improve the effectiveness of immunotherapy.

Keywords: antigen presentation; autophagy; immune cells; immunogenic cell death; immunotherapy; tumor microenvironment.

Figure 1

Hot and cold TME. The tumor microenvironment (TME) is divided into the immune desert (cold) and immunoinflammatory (hot) phenotypes. In the immune desert phenotype, the absence of T cells in the tumor may be due to the lack of tumor antigens and antigen-presenting cells (APC), the secretion of immunosuppressive molecules such as TGF-β and IL-10, and the infiltration of immunosuppressive cells including MDSC, M2 macrophages, and Treg. In addition, abnormal angiogenesis and excessive ECM also play an important role in the formation of cold TME. The immunoinflammatory phenotype is thought to be a prominent infiltration of cytotoxic T lymphocytes (CTLs) in the core of the TME, with activated antigen-presenting cell (APC) markers and type 1 interferon (IFN) responses.

Figure 2

The different types of autophagy. Proteins, organelles, and other cellular components are sequestered in a newly formed isolation membrane. This isolation membrane then swells and seals to form a double membrane-bound vesicle, the autophagosome. Degradation of the autophagosome occurs when the autophagosome fuses with the lysosome. In secretory autophagy, Autophagosomes fuse with multivesicular bodies to produce double-membrane bodies that can fuse with the plasma membrane and secrete cargo into the extracellular space. Furthermore, late and early autophagy inhibitors have different effects on secretion.

Figure 3

Crosstalk between autophagy and TME features. Hypoxic stress is a typical feature of TME, which triggers the abnormal vasculature and the alteration of the three-dimensional stromal environment. In response to these stresses, autophagy can be induced by HIF-1, VEGF, and TGF-β to promote tumor cell survival, enhance differentiation of normal fibroblasts to CAF, promote dense ECM formation, inhibit immune cells infiltration and vascular normalization, impair CTL and NK cell-mediated anti-tumor immune responses, and convert hot TME to cold.

Figure 4

Targeting autophagy burns the cold TME. TME regulation mechanism includes antigen signal release, antigen presentation, antigen recognization, as well as immune cell infiltration. Autophagy plays a key role in these processes. (A) Secretory autophagy promotes ICD to burn the cold TME. (B) Autophagy inhibits the MHC-I expression on the surface of tumor cells and DC to inhibit antigen presentation. (C) Autophagy inhibits PD-L1 expression on the surfaces of tumor cells. (D) Autophagy inhibits CD8⁺ T cells and NK cells infiltration and tumor-killing effect and promotes the survival and development of Treg and MDSC. Autophagy promotes TAM polarize to M2 and enhances the immunosuppressive function of macrophages.