Autophagy in tumor immune escape and immunotherapy.

Introduction

Cellular autophagy, a fundamental process of material recycling metabolism in eukaryotic organisms, involves the encapsulation of damaged proteins or organelles within double-membraned autophagic vesicles, which are subsequently transported to lysosomes for degradation [ 1 , 2 ]. It has been widely reported that autophagy plays a pivotal role in the pathogenesis and therapeutic treatment of a variety of diseases, including tumors [ 3 , 4 ]. Autophagy exhibits a dual impact on tumor progression, whereby the modulation of autophagy in distinct types of cells results in variable effects on tumor growth [ 5 , 6 ]. Thus, proper regulation of autophagy may be a potential pathway for tumor treatment.

The tumor immune microenvironment (TIME) is a complex and dynamical network that significantly influences tumor progression. Tumor cells achieve immune escape by evading immune surveillance through various mechanisms, including deletion or down-regulation of tumor antigens to reduce their immunogenicity and suppression of immune responses [ 7 , 8 ]. Regulation of immune function exerts significant influence on tumorigenesis and development, with immunotherapy gradually emerging as a key strategy in anti-tumor therapy [ 9 ]. Currently, the main classes of immunotherapeutic agents in clinical use are immune checkpoint inhibitors, specifically those targeting the programmed cell death ligand 1 (PD-L1)/programmed cell death protein 1 (PD-1) axis and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) [ 10 – 13 ]. The utilization of immune checkpoint inhibitors alone or in conjunction with cytotoxic drugs and targeted therapies has demonstrated enhanced therapeutic efficacy in tumor management, extending patient survival durations and ameliorating quality of life [ 14 , 15 ]. However, the clinical benefits of immunotherapy are not universal. Challenges such as immune resistance and severe adverse effects impeding its widespread clinical utility [ 16 ]. Recent studies suggest that autophagy plays a pivotal role in modulating immune responses and the efficacy of antitumor immunotherapy by regulating the function of tumor cells or immune cells, as well as the production of cytokines [ 17 – 20 ]. This study presents a comprehensive review elucidating the critical role of autophagy in shaping tumor immunity and influencing immunotherapeutic responses.

Cellular autophagy

Cellular autophagy, a vital process of eliminating dysfunctional cellular components and recycling metabolic byproducts, mainly occurred within lysosomes [ 21 ]. It can be categorized into three primary types: macroautophagy, microautophagy, and chaperone-mediated autophagy, with macroautophagy being the most extensively studied pathway [ 22 ] (Fig. 1 ). As a fundamental regulatory mechanism, autophagy allows organisms to adapt to environmental stress and maintains a balance between cell survival and death [ 23 ]. The initiation phase of autophagy is primarily orchestrated by the ATG1/ULK1 complex, composed of ATG1/ULK1, ATG13, FIP200, and ATG101 proteins [ 21 ]. mTOR kinase serves as a critical regulatory in this process, inhibiting the activity of the ULK complex through the phosphorylation of ULK1 and ATG13, thereby suppressing the onset of autophagy [ 21 ]. AMPK and p53 signaling promote autophagy by negatively regulating mTOR activity. Additionally, conditions such as starvation and cellular stress enhance autophagy by inhibiting mTOR [ 21 ]. The nucleation phase is primarily driven by the VPS34 (PIK3C3)—VPS15—Beclin-1 complex [ 24 ]. There exist two functionally different VPS34—VPS15—Beclin-1 complexes. In the case of complex I, ATG14 binds to the complex and stimulates the synthesis of PI3P, along with the recruitment of other autophagy-associated proteins, thereby promoting autophagosome formation. Complex II, on the other hand, is a complex that contains UVRAG mainly involved in promoting autophagosome maturation, endocytosis, and cytokinesis [ 25 ]. It is important to note that the Bcl-2 protein can prevent the initiation of autophagy by inhibiting Beclin-1 activity; alleviating this inhibition activates autophagy [ 21 , 24 ]. Subsequently, ATG genes regulate the elongation and completion/closure of autophagosome. ATG8/LC3 is cleaved by ATG4 to produce LC3-I, which is then activated by ATG7 and translocated to ATG3, and finally modified by phosphatidylethanolamine to form LC3-II with the help of the ATG12-ATG5- ATG16L1 complex [ 26 , 27 ]. The lipidated form, LC3-II, associates with autophagosome membranes, promoting autophagosome formation [ 21 , 28 ]. In this process, p62, which acts as a bridge linking LC3 and polyubiquitinated proteins, is selectively wrapped into the autophagosome, after which it is degraded by proteohydrolases in the autophagic lysosome [ 21 , 28 ]. Thus, the amount of p62 is negatively correlated with autophagic activity [ 26 ]. Afterward, nascent autophagosomes fuse with vesicles that originate from endolysosomal compartments prior to the formation of degradative autolysosomes, and this process is called autophagosome maturation. This stage is mainly regulated by the cooperative actions of ATG8 family members, tethering factors, Rab proteins and SNARE complexes [ 21 , 24 , 29 ]. 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 )

Furthermore, mitophagy, a specialized form of autophagy targeting damaged mitochondria for degradation, plays a pivotal role in maintaining mitochondrial homeostasis [ 30 ]. The molecular mechanisms of mitophagy involve both ubiquitin-dependent pathways (such as the PINK1/Parkin and non-Parkin ubiquitin-dependent pathways) and ubiquitin-independent pathways (like the NIX, BNIP3, and FUNDC1 pathway) [ 30 ]. The various molecular pathways of mitophagy interact intricately to control mitochondrial quantity and cellular metabolic homeostasis. Apart from the traditional mitophagy mechanism, numerous studies in recent years have confirmed regulatory methods that are different from the classic pathways. For example, Jose et al. found that NDP52 binds to the ULK1 complex through its interaction with FIP200 and initiates autophagy in an LC3-independent manner [ 31 ]. OPTN can bind to ATG9A to induce mitophagy, and blocking this binding will lead to a reduction in mitophagy [ 32 ]. Moreover, OPTN can also initiate mitophagy by binding to the PI3K complex with the help of TBK1 in a ULK1/2-independent manner [ 33 ]. In addition, apart from the well-known LC3, NIX and BNIP3 can initiate autophagy by directly binding to WIPIs [ 34 , 35 ]. These studies have revealed more mechanisms of how different proteins cooperate to regulate mitophagy, deepening our understanding of this process.

Autophagy undergoes dynamic changes at different stages of tumor development [ 36 – 39 ]. It is generally accepted that autophagy exerts a tumor suppressor role in the early stages of tumorigenesis by inhibiting tissue damage and inflammatory responses. And as the tumor growth, autophagy is enhanced due to inadequate vascularization and limited nutrient supply, forcing cancer cells to rely on autophagy for sustenance [ 40 ]. To leverage autophagy effectively for tumor therapy, an in-depth comprehension of the molecular mechanisms governing autophagy during tumor initiation and progression is imperative for designing targeted treatment strategies [ 37 ].

Tumour immune escape and immune therapies resistance

The immune system plays a crucial role in maintaining human health and resisting the occurrence and progression of tumors. Under normal circumstances, immune cells in the immune system, including T cells, neutrophils, dendritic cells (DCs), natural killer (NK) cells, macrophages, and B cells, work together in a precise manner to identify tumor-specific antigens and produce cytotoxic factors, effectively eliminating cancer cells and preventing tumor formation and expansion. However, tumor cells can evade immune system surveillance to avoid recognition and attack. This immune evasion is primarily achieved through alterations in the tumor cells themselves and changes in the immune microenvironment, which include: (1) reduced immunogenicity; (2) antigen modulation or loss; (3) low expression of major histocompatibility complex (MHC) class molecules; (4) prevention of apoptosis; (5) lack of costimulatory molecules; (6) recruitment of immunosuppressive cells; and (7) secretion of immunosuppressive factors.

In light of the understanding of immune evasion mechanisms, tumor immunotherapy has rapidly developed in recent years, aiming to effectively kill tumor cells by activating or enhancing the immune system. Current major immunotherapeutic approaches include immune checkpoint inhibitors, adoptive cell therapy, and tumor vaccines. Among these, immune checkpoint inhibitors, such as PD-1/PD-L1 and CTLA-4 blockers, are the most widely used in clinical applications and have demonstrated significant efficacy [ 10 ]. For example, studies such as KEYNOTE-189 and KEYNOTE-407 have indicated that the combination of PD-1 monoclonal antibody pembrolizumab with standard chemotherapy results in improved overall survival in patients with non-small cell lung cancer (NSCLC), in comparison to single-agent chemotherapy [ 12 ]. Additionally, Cadonilimab, a PD-1/CTLA-4 dual monoclonal antibody, has shown promising objective response rates and safety profiles in solid tumors [ 13 ]. However, there are still issues with low efficiency and immune resistance [ 41 ]. Immune resistance can be classified into primary resistance and acquired resistance, making the overcoming of immune resistance a pressing issue that needs to be addressed [ 42 ].

Autophagy is deemed a significant factor in both immune evasion and immune resistance [ 21 ]. Autophagy can have dichotomous roles: on one hand, it may enhance anti-tumor immune responses through autophagy in T cell subsets and support tumor antigen presentation in tumor cells, thereby assisting in tumor immune therapy [ 37 ]. On the other hand, autophagy may facilitate tumor cell survival, degrade tumor antigens, enhance regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), thereby contributing to tumor immune escape and drug resistance [ 3 ]. Thus, appropriate modulation of autophagy to reduce immune escape, improve immunotherapy efficacy and overcome drug resistance may eventually leads to beneficial clinical outcomes.

Autophagy and cancer cells (Table 1 )

Autophagy and its regulatory role in PD-L1 expression in tumor cells (Fig. 2 )

PD-L1, also known as B7-H1, is a prominent member of the B7 family, frequently expressed on the surface of various tumor cells. Its interaction with the PD-1 receptor on T cells induces T-cell apoptosis, dysfunction, and exhaustion, thereby inhibits T cells activation and proliferation, which ultimately facilitates tumor immune evasion [ 43 , 44 ]. Clinically, immune checkpoint inhibitors that target PD-1 and PD-L1 have emerged as the most popular therapeutic options, aimed at enhancing the immune system's ability to attack tumors by restoring T-cell activity [ 45 ].

Recent studies reveal that the autophagic degradation of PD-L1 within tumor cells can enhance anti-tumor immunity, augment T-cell cytotoxicity, and inhibit immune evasion. For instance, PPARγ contains a microtubule‐associated protein 1A/1B‐LC3 interacting region motif, which facilitates the autophagic degradation of PD-L1 in lysosomes, subsequently enhancing T-cell activity against NSCLC [ 46 ]. Similarly, mTORC1 inhibition has been shown to induce PD-L1 autophagic degradation in p53-deficient hepatocellular carcinoma (HCC), thus, combining mTOR inhibitors and PD-L1 monoclonal antibodies can enhance anti-tumor efficiency [ 47 ]. Accordingly, it is conceivable that inhibition of autophagy can inhibit PD-L1 degradation leading to its up-regulation. Indeed, study has shown that inhibition of selective autophagic degradation mediated by the p62 pathway leads to PD-L1 accumulation [ 48 ]. TRIM14 recruits the deubiquitinating enzyme USP14, USP14 deubiquitylated PD-L1 and thus prevents its recognition as cargo by p62 for autophagic degradation [ 49 ]. Additionally, CXCL12 mediates immune escape in bladder cancer by upregulating PD-L1 through autophagy inhibition; the combined application of a CXCL12 receptor blocker and PD-1/PD-L1 blockers has shown a more pronounced effect in inhibiting PD-L1 expression and enhancing the anti-tumor immune response [ 50 ]. Furthermore, IL-17A inhibits autophagy via the ROS/Nrf2/p62 pathway, thereby promoting PD-L1 expression in cancer cells and driving NSCLC progression [ 51 ]. Whereas overexpression of miR-34a in bladder cancer cells could prevent the autophagy blockade-induced PD-L1 upregulation [ 52 ]. Apart from preventing PD-L1 degradation, autophagy inhibition can also enhance PD-L1 transcription. For example, TSPO mediates autophagy inhibition through interaction with p62, leading to its accumulation; this accumulation competes with KEAP1 to prevent Nrf2 degradation, thereby promoting Nrf2-mediated transcriptional upregulation of PD-L1 [ 53 ].

However, there are studies suggesting that autophagy activation can also upregulate PD-L1. In lung cancer patients with depression, activation of the 5HT1aR can upregulate PD-L1 expression by activating tumor autophagy and p-STAT3 signaling, contributing to an immunosuppressive environment [ 19 ]. The overexpression of ATG7 primarily enhances PD-L1 protein levels by promoting autophagy-mediated degradation of FOXO3a, resulting in the downregulation of miR-145, which stabilizes PD-L1 mRNA [ 54 ].

Several pharmacological agents have been identified that inhibit PD-L1 expression by promoting autophagy. For example, Sunitinib, Andrographolide, and zosuquidar enhance p62-dependent selective autophagic degradation of PD-L1, thereby boosting anti-tumor immunity [ 55 – 57 ]. Curcumin, a well-known compound, can induce autophagy to suppress PD-L1 expression, enhancing nucleolin-mediated T-cell activity in triple-negative breast cancer [ 58 ]. Additionally, temsirolimus inhibits the secretion of small extracellular vesicle PD-L1and cellular PD-L1 expression in breast cancer cells by activating autophagy, thereby stimulating anti-cancer immunity through increased numbers and activation of CD4 + and CD8 + T cells [ 59 ]. Moreover, Sigma1 inhibitors act as potential novel immune modulators by sequestering and eliminating PD-L1 through autophagy in both of breast and prostate cancer cells [ 58 ]. Vemurafenib suppresses PD-L1 expression on tumor cells via Golgi-mediated autophagy which increases T lymphocyte infiltration and enhances anti-tumor immune responses [ 60 ]. Additionally, amlodipine induces autophagic degradation of PD-L1 by blocking calcium flux, thereby counteracting PD-L1-dependent tumor immune evasion [ 61 ]. Rigosertib activates AMPK-ULK1, promotes autophagy-dependent PD-L1 degradation, and synergizes with CTLA-4 antibody in colorectal cancer (CRC) therapy [ 62 ]. The compound USP24-i-101 inhibits the expression of ABCG2 and PD-L1 via autophagy induction, thereby suppressing drug resistance in lung cancer [ 63 ]. Celastrol exerts antitumor effects on clear cell renal cell carcinoma by activating autophagy to downregulate PD-L1 expression and inducing immunogenic cell death (ICD) [ 64 ]. Likewise, pharmacological inhibition of autophagy can upregulate PD-L1 expression. Our study has shown that cinchonine upregulates PD-L1 expression in lung cancer cells by inhibiting autophagy, and combined administration of anti-PD-L1 inhibitors and cinchonine significantly reduces tumor growth [ 65 ]. In bladder cancer cells, autophagy inhibitors such as Chloroquine (CQ) and Bafilomycin A1 inhibit autophagy, leading to increased PD-L1 expression and immune suppression via the ERK-JNK-c-Jun signaling pathway [ 52 ]. What’s more, aspartame potassium upregulates PD-L1 expression through autophagic inhibition, mediating immune evasion in HCC [ 66 ].

Mitophagy in tumor cells can influence PD-L1 expression through the autophagy pathway, thereby affecting the immune response. The distribution pattern of PD-L1 is regulated by the ATAD3A-PINK1 axis, wherein PINK1 recruits PD-L1 to mitochondria for degradation via mitophagy [ 67 ].

Regulation of immune checkpoints MHC-I expression in tumor cells by autophagy (Fig. 3 )

MHC molecules, also known as human leukocyte antigens, are expressed on the surface of cells that recognize and bind antigens, which are then presented to T cells to initiate and regulate immune responses [ 68 ]. MHC molecules are divided into two major classes: MHC class I (MHC- I) is widely expressed in a wide variety of cells, whereas MHC class II (MHC- II) is found predominantly on the surface of antigen-presenting cells [ 68 ]. During tumor progression, the MHC antigen-presenting process is impaired by different means, leading to tumor immune escape [ 69 ]. Restoring the function of MHC molecules, thereby enhancing the specific recognition and attack of T cells against tumors, is currently the direction of many immunotherapeutic strategies [ 70 ].

Most current findings below suggest that promotion of autophagy leads to downregulation of MHC-I expression, thereby inhibiting the immune response. In approximately 60% of pancreatic cancers, MHC class I molecules are found at lower-than-normal levels or are completely absent, primarily due to autophagy-induced degradation [ 71 ]. Treatments involving progranulin, depletion of NDRG1 or CH25H all reduce MHC-I expression and antigen presentation through autophagy induction in pancreatic cancers [ 72 – 74 ]. Mechanistic studies have shown that autophagy cargo receptor NBR1 induces MHC-1 degradation by binding to MCH-1 and recruiting it to autophagic vesicles in pancreatic cancers [ 71 ]. Further studies have shown that MHC-1 is degraded in this mechanism-dependent manner in a variety of tumors, and that HIF1A-AS2, RIPK2 and LC3 all can regulate MHC-1 expression by modulating this mechanism [ 75 , 76 ]. In CRC, CXCL1 promotes immune evasion through enhancing autophagy-mediated MHC-I degradation [ 77 ]. IRGQ promotes tumor immune evasion by directing misfolded MHC-I molecules to the lysosome for degradation, a process that relies on the interaction of IRGQ with autophagy-related proteins GABARAPL2 and LC3-II [ 78 ]. Inhibiting of LSD1 activity can suppress autophagy, leading to an increase in the expression of MHC-I molecules, thereby improving the TIME in NSCLC [ 79 ]. Deficiency of PCSIN1 inhibits gastric cancer progression by upregulating MHC-I through the autophagy inhibition [ 80 ]. Berbamine has been shown to enhance MHC-I expression by inhibiting autophagy in malignant melanoma, thereby restraining the tumor's immune evasion [ 81 ]. However, it has also been shown that autophagy plays a positive or bidirectional role in regulating MHC expression. For example, autophagy induced by radiation increases MHC-I expression and increased CD8 + T cell infiltration during a single radiation dose from 2 to 20 Gy in a dose-dependent manner [ 82 ]. Moreover, in melanoma cells, autophagy negatively regulates MHC-I antigen expression; however, this process can be reversed with the presence of IFN-γ [ 83 ].

Tumor cell autophagy modulates the immune response in a variety of other ways (Fig. 4 )

Autophagy modulates immune responses in tumor cells by influencing the expression of various surface molecules beyond PD-L1 and MHC. For instance, studies in pancreatic cancer have shown that autophagy inhibition leads to tumor antigen accumulation, which activates DCs; however, it also induces the expression of immune checkpoint LAG3 and leads to CD8 + T cell exhaustion [ 84 ]. In NSCLC, autophagy inhibition upregulates human leukocyte antigens-I expression, enhancing the cytotoxicity of activated T cells [ 85 ]. Additionally, the glutamine metabolism inhibitor V9302 has been found to reduce B7H3 expression and promote granzyme B production in CD8 + T cells through autophagy promotion [ 86 ]. In melanoma, radiotherapy boosts anti-CTLA-4 immunotherapy efficacy by facilitating autophagy-induced translocation of mannose-6-phosphate receptors to the cell surface [ 87 ].

Cytokines are important mediators of intercellular signaling and can regulate immune cell functions in many ways, such as proliferation, migration, and differentiation [ 88 ]. Autophagy can regulate cytokine expression in tumor cells, influencing tumor immunity. In the 4T1 and Py8119 mouse models, glycolytic restriction inhibited LAP expression through activation of AMPK-ULK1 and autophagy, and down-regulation of LAP decreased G-colony stimulating factor (CSF) and GM-CSF expression and thus MDSCs recruitment, which, in turn, enhanced the anti-tumor activity of T cells and inhibited tumor proliferation and metastasis [ 89 ]. Loss of the autophagy gene Beclin1 in tumors drives elevated CCL5 expression, recruiting cytotoxic NK cells that inhibit tumor growth [ 90 ]. By inhibiting ULK1, Rocaglamide inhibits autophagy, thereby restoring NK cell-derived GZMB (granzyme B) levels in NSCLC cells, which in turn enhances NK-mediated killing [ 91 ]. In EGFR-mutant LUAD, ARID1A deficiency suppresses autophagy, promoting type I interferon production and improving ICIs response [ 92 ]. What’s more, gut microbiota-derived short-chain fatty acids activate cancer cell autophagy, increasing CCL20 chemokine levels, which polarizes macrophages toward the pro-tumor M2 phenotype, facilitating prostate cancer progression [ 93 , 94 ].

In addition to cytokines, autophagy affects tumor immunity by modulating metabolite secretion. In oral squamous cell carcinoma, F. nucleatum binding to GalNAc triggers autophagy, downregulating TBC1D5 and causing GLUT1 accumulation on the plasma membrane; this promotes lactate secretion, driving tumor-associated macrophages (TAMs) formation and cancer progression [ 95 ]. In cervical cancer, IFN-γ treatment upregulates IDO-1 expression, leading to kynurenine accumulation, which induces autophagy that further promotes phagocytic activity and activation of macrophages [ 96 ].

ICD refers to the process whereby tumor cells transition from non-immunogenic to immunogenic states upon death, thus inducing an anti-tumor immune response [ 97 ]. During ICD, damage-associated molecular patterns (DAMPs) are released, such as High Mobility Group Box 1 (HMGB1), ATPs, and heat shock proteins (HSP70, HSP90), along with the exposure of calreticulin on the cell surface [ 98 ]. These DAMPs play a crucial role in activating anti-tumor immunity. Autophagy, apoptosis, necrosis, and other forms of cell death, collaborate within the ICD process to ensure effective immune activation [ 99 ]. Methionine enkephalin, oncolytic adenovirus OBP-702, Piceatannol, Thiostrepton and Oncolytic adenovirus with temozolomide, have all been reported to induces autophagy and promote the secretion of DAMPs, thereby amplifying the immune response [ 100 – 104 ]. However, it’s also reported that Brucine induced the release of DAMPs through autophagy inhibition, regulating the TIME of CRC [ 105 ].

Emerging studies further highlight autophagy’s involvement in tumor immunomodulation. Imipramine promotes T-cell recruitment by activating autophagy, and VEGF inhibitors provide a more suitable environment for T-cell activation; therefore, the combination of both can efficiently activate immunity and inhibit the growth of glioblastoma [ 106 ]. In CRC, FuFangChangTai decoction activates autophagy to promote the secretion of autophagosomes, leading to the activation of macrophages toward M1 [ 107 ]. PTEN loss in melanoma cells induces tumor cells to evade T cell killing by inhibiting autophagy [ 108 ]. In NSCLC, SKIL upregulates TAZ, which induces autophagy and inhibits the STING pathway, promoting immune evasion and tumor growth [ 109 ]. Similarly, TRABID activation of autophagy reduces Tbk1 and Irf3 phosphorylation, suppressing cGAS/STING-dependent anti-tumor immunity [ 110 ].

Targeting mitophagy also offers potential in tumor immunity. FUNDC1 mediated mitophagy to suppress the production of ROS and IL-1β and regulate immunosuppression [ 111 ]. MEK inhibitors have shown promise by promoting mitophagy and TLR9 activation, leading to CXCL10 expression and CD8 + T cell recruitment [ 112 ]. Icaritin induces both mitophagy and cell apoptosis, stimulating ICD and thus activate T cells, which contribute to a more effective anti-tumor response [ 113 ].

Autophagy and immune cells (Table 2 )

Tumor-infiltrating immune cells include T cells, macrophages, NK cells, MDSCs, DCs, B cells and neutrophils [ 114 ]. Among these immune cells, autophagy plays an important role in anti-tumor immunity by influencing proliferation, activation and differentiation [ 115 ]. We will review the functions of autophagy in immune cells below. It is worth mentioning that many of the relevant studies were not performed in tumor models, but we still list them because we believe that the immune regulatory mechanisms are connected. Fully interpreting these studies will help us to modify immune cells by targeting autophagy in the future to enhance anti-tumor immunity (Fig. 5 ). 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 )

Autophagy in T cells

Cytotoxic T Lymphocytes (CD8 + T cells) are the cornerstone of anti-tumor immunity, directly eliminating tumor cells by recognizing tumor-specific antigens [ 116 ]. Helper T Cells (Th, CD4 + T cells) support this response by secreting cytokines. Studies involving autophagy-related genes such as ATG3, ATG5, ATG7, Beclin-1, and PI3K-deficient T cells and mouse models have demonstrated that autophagy defects lead to increased cell apoptosis and ineffective T cell proliferation, ultimately impairing the T cell immune response [ 116 ]. Specifically, autophagy deficiency can prevent the degradation of CDKN1B (a major negative regulator of the T cell cycle) following TCR stimulation, resulting in the inability of CD8 + T cells to progress into the S phase [ 117 ]. In TIME, oxysterols induce T cell cholesterol deficiency through inhibiting the SREBP2 pathway and activating of the LXR pathway, which in turn inhibits T cell proliferation and triggers autophagy-mediated cell apoptosis, resulting in T cell depletion and dysfunction [ 118 ]. In ovarian cancer patients and tumor-bearing mice, tumor-produced lactate inhibits the expression of FIP200, resulting in autophagy defects in naïve T cells, excessive activation of mitochondria, and elevated levels of ROS, thereby promoting T cell apoptosis and immune evasion [ 119 ]. Additionally, BCL10 interacts with p62 to mediate selective autophagy in effector T cells and regulate the TCR signaling pathway towards the NF-κB signaling pathway to maintain T-cell homeostasis and function [ 120 ].

In addition to regulating proliferation and apoptosis, autophagy affects T cell differentiation, activation, stemness, infiltration, and other aspects. Unlike the previously mentioned, Xu et al. identified that ATG5 or ATG7 depletion has no significant impact on effector T cells function, but impairs the formation of memory T cells [ 121 ]. Other studies showed that T cells with ATG5 deficiency undergo a marked shift to an effector memory phenotype, secreting increased amounts of IFN-γ and TNF-α [ 116 , 121 ]. Furthermore, autophagy inhibition due to ATG5 deficiency induces CD8 + T cell glucose metabolism, which promotes anti-tumor immunity of CD8 + T cells [ 122 ]. Liver-resident CD8 + T cells exhibit a higher basal autophagy rate, and inhibiting autophagy could result in the accumulation of depolarized mitochondria, promoting CD8 + T cell exhaustion [ 123 ]. Additionally, IL-15 in primary liver cells may induce CD8 + T autophagy and tissue residency [ 123 ]. Moreover, it has been discovered that the activation of effector T cells requires the induction of autophagy to supply energy, and restoration of autophagy (even temporarily) has been shown to sustain T cell infiltration [ 115 ].Elevated K + levels trigger a starvation response in CD8 + T cells, reducing nutrient utilization and inducing autophagy, which in turn triggers T cell stemness [ 124 ]. Decreased mitophagy activity in CD8 + T cells leads to the accumulation of depolarized mitochondria, pushing CD8 + T cells towards exhaustion [ 125 ]. As a key participant in autophagy, PIK3C3/VPS34 deficiency decreases active mitochondria levels in activated T cells, resulting in reduced glycolysis in CD4 + T cells and inhibiting their differentiation into Th1 cells [ 126 ]. CD4 + T cells lacking ATG3 or ATG5 show selective repression of their differentiation into Th9 cells due to autophagy blockade, while this blockade enhances the anticancer functions of Th9 cells in vivo [ 127 ].

Tregs play a significant role in tumor immune evasion and resistance to immunotherapy through their immunosuppressive effects [ 128 ]. It’s reported that autophagy is active in Tregs, and the absence of essential autophagy genes such as ATG5 and ATG7 results in dysfunctional Tregs [ 129 , 130 ]. Mechanistically, defective autophagy in Tregs can upregulate the upstream autophagy signal mTORC1, MYC function, and glycolytic metabolism, resulting in Tregs dysfunction [ 130 ]. The mTORC1/C2 inhibitor AZD8055 inhibits autophagy levels and enhances the mitochondrial stress response in Tregs, leading to mitochondrial dysfunction, inhibition of Tregs proliferation, and attenuation of their immune suppressive function [ 131 ]. Moreover, CTLA-4, highly expressed on Tregs plays a crucial role in mediating immune suppression capabilities [ 11 , 128 , 132 , 133 ]. Studies suggests that autophagy suppression contributes to resistance to CTLA-4 blockade in melanoma, proposing the potential therapeutic synergy of autophagy induction with CTLA-4 inhibitors [ 134 ]. Research also indicated that CTLA-4 in Tregs can be degraded through the autophagy-lysosome pathway, with autophagy inhibitors like CQ identified as inhibitors of CTLA-4 degradation [ 135 ]. In conclusion, the expression levels of CTLA-4 are closely related to autophagy, which have an impact on the TIME and immune responses.

Autophagy in macrophages

Macrophages are specialized phagocytes capable of presenting antigens by phagocytosis [ 136 ]. TAMs are mainly derived from peripheral blood monocytes and tissue-resident macrophages [ 137 ]. They can be polarized by the TIME into two distinct phenotypes: pro-inflammatory and anti-cancer M1 types and anti-inflammatory and pro-cancer M2 types [ 137 ]. Autophagy played a pivotal role in regulating macrophage polarization. For instance, the inhibition of macrophage autophagy deactivated the NF-κB pathway by promoting the ubiquitination degradation of TAB3, thereby facilitating M2-like polarization of macrophages and promoting HCC progression [ 138 ]. Similarly, the activation of the autophagy inhibitor mTOR encourages M2 phenotype. TSC2, as a negative regulator of mTOR signaling, knockdown also causes TAMs M2 polarization, thus promoting tumor angiogenesis [ 139 ].What’s more, TRAF2 also been reported as a M2 polarization inducer by inhibiting TAMs autophagy [ 140 ]. Tumor cell-derived exosomal RNF126, an E3 ubiquitin ligase, mediates PTEN ubiquitination degradation in macrophages to activate the PI3K/AKT signaling and inhibit autophagy, thus promoting macrophage migration and M2 polarization [ 141 ]. In contrast, the activation of Nod1 promotes autophagy-dependent reprogramming of macrophages toward an alternative phenotype, facilitating CRC progression [ 142 ]. Cryptotanshinone has been shown to remodel TAM from M2 to M1 by downregulating the TRAF6-mediated ASK1/JNK/autophagy signaling pathway [ 143 ]. Sorafenib induces macrophage autophagy, thus suppressing the expression of the M1 marker CD80 and phagocytosis [ 144 ].

Autophagy also influences macrophage aggregation; study has reported that inhibition of autophagy promotes macrophage self-recruitment through activation of CCL20-CCR6 signaling for HCC progression [ 145 ]. In addition, Cucurbitacin IIa enhanced macrophage autophagy induced by LPS, suppressing macrophage proliferation and migration [ 146 ]. However, it’s also found that recombinant capsid protein VP1 stimulates macrophage migration by autophagy induction via WIPI1and WIPI2 [ 147 ].

Furthermore, autophagy modulates the antigen presentation function of macrophages. Asparaginase activates AKT/mTOR and suppresses ERK1/2 signaling to suppress autophagy thus deterring macrophage phagocytosis, cytokine secretion, and MHC-II expression [ 148 ]. Recombinant human arginase I and Gemcitabine downregulate autophagy that impairs macrophage functions such as proliferation, phagocytosis and MHC-II expression, leading to immune suppression [ 149 , 150 ]. Pb was found to increase MHC-II surface expression and induce autophagy in macrophages, which in turn modulates the immune response [ 151 ]. In contrast, TIM-4 activates autophagy in macrophages after the uptake of apoptotic tumor cells, leading to a reduction in antigen presentation [ 152 ].

In addition to these roles, autophagy influences macrophage cytokine secretion. ATG12-ATG3 interactions are essential for autophagosome formation, and compounds that target this interaction can attenuate IL-1β secretion by macrophages [ 153 ].

Autophagy in monocytes

The differentiation of monocytes into macrophages was a caspase-dependent process triggered by CSF-1 [ 154 ]. Research has shown that CSF-induced differentiation of monocytes into macrophages is autophagy-dependent, and that knockdown of autophagy-related genes (such as ATG5, ATG7, and Beclin-1) or pharmacological inhibition of autophagy impedes this differentiation process [ 154 , 155 ]. Additionally, CSF can induce autophagy by activating MAPK/JNK to mediate the disassociation of Beclin-1 from BCL2, promoting monocyte survival and differentiation into macrophages [ 156 ]. Therefore, inhibiting autophagy could effectively hinder CSF-induced monocyte differentiation into macrophages, offering a potential approach for clearing macrophages in tumor treatment [ 156 ]. Additionally, research has shown that hydroxyproline enhances PD-L1 expression through autophagy inhibition [ 157 ]. However, autophagy activation also has the potential to promote monocyte differentiation to anti-tumorigenic macrophages. ER stress increases the expression of CD244 in monocytes and subsequently inhibits the generation of Ly6Clow anti-tumor type macrophage by suppressing autophagy, while CD244 deficiency activates monocyte autophagy, which promotes the generation of anti-tumor macrophages [ 158 ].

The autophagy regulation of MDSCs

MDSCs are immunosuppressive cells derived from the myeloid lineage, classified into monocytic MDSCs (M-MDSCs) and granulocytic MDSCs (G-MDSCs) [ 159 ]. MDSCs are closely related to tumor progression and metastasis, and emerging evidence indicates that autophagy within MDSCs significantly influences tumor immune responses [ 159 ]. Targeting MARCH1 E3 ubiquitin ligase in autophagy-deficient M-MDSC leads to significant upregulation of MHC-II on its surface, which reduces the suppressive activity of M-MDSC and results in significant tumor shrinkage [ 160 ]. Additionally, HMGB1 contributes to tumor progression by boosting MDSCs viability through autophagy induction [ 161 ]. β2-AR signaling enhances autophagy in MDSCs and activates the arachidonic acid cycle, which promotes the release of the immunosuppressive mediator PGE2 [ 162 ]. Furthermore, SOCS3-deficiency activates the Wnt/mTOR pathway, leading to autophagy repression that arrests early-stage MDSCs differentiation in the myeloid lineage [ 163 ]. It has been found that LCL521 targets lysosomes to activate cathepsin B and cathepsin D, resulting in interrupted autophagy and ER stress that culminated in MDSC death [ 164 ]. In general, cathepsin B and cathepsin D activation promotes autophagy [ 165 ]. The reason for this contrasting outcome is not clear, we speculate that it may be related to the different activation times of the two proteins, or it may be due to the interaction with mTOR, PI3K-Akt and other signaling pathways after its activation. Continuous optimization of experimental conditions and analysis of signaling pathways using a multi-omics system may help to clarify the cause of this discrepancy. Interestingly, G-MDSCs exhibit autophagy upregulation when exposed to LPS [ 166 ]. Under such circumstances, inhibiting autophagy promotes the activation of STAT-3 signaling, thereby facilitating the accumulation and immunosuppressive functions of G-MDSCs [ 166 ].

Autophagy regulation in DCs

DCs are considered the most powerful antigen-presenting cells. Autophagy plays a crucial role in antigen processing and presentation within DCs, thereby influencing the immune response to tumor cells. Foxp3 + Tregs promote the activation of the PI3K/AKT/mTOR axis and inhibit autophagy in DCs through a CTLA-4-dependent manner, affecting antigen presentation and effectively ameliorates autoimmune responses in vivo [ 167 ]. ATG5-mediated autophagy is also essential for DCs loading of extracellular microbial antigens onto MHC-II [ 168 ]. Moreover, treatment with IL-4 during DCs differentiation promotes MHC-II-mediated endogenous antigen presentation by inducing autophagic flux through regulation of mTORC1 signaling and upregulation of RUFY4 [ 169 ]. Knockdown of TFEB or TFE3 exacerbates autophagy inhibition in arsenic-exposed DCs while simultaneously reducing the expression of antigen-presenting molecules MHC I and MHC II [ 170 ]. Additionally, β-glucan-induced autophagy in DCs is a key mechanism for their maturation; it enhances the expression of MHC-II, CD80, and TNF-α secretion, while increasing iNOS production; this process promotes the priming and differentiation of Th1 and cytotoxic T lymphocytes in vitro [ 171 ]. Docosahexaenoic acid has been shown to activate autophagy in PBMCs and DCs, thus potentially acting as immune stimulator and enhancing processing and presentation of tumor antigens by DCs [ 172 ]. However, study also showed that LC3-II lipidation mediates AAK1 binding to MHC- I, leading to endocytosis and autophagic degradation of MHC-I in DCs thus suppressing T cell immune responses, whereas deletion of ATG5 and ATG7 inhibits MCH-I internalization by disrupting AAK1 binding to MHC-I [ 173 ]. In addition, it has been suggested that autophagy was prominent only in DCs subtypes specialized for cross-presentation, with its effects more pronounced when the antigen was a soluble protein, while being negligible for cell-associated antigens or those delivered through receptor-mediated endocytosis [ 18 ].

Autophagy of neutrophils

Neutrophils are the most abundant leukocytes in the human innate immune system and play a bidirectional role in tumor progression. The role of neutrophil autophagy in this context is similarly dual-faceted. Exosomes derived from gastric cancer cells have been shown to induce autophagy in neutrophils through the HMGB1/TLR4/NF-κB signaling pathway, thereby promoting the metastasis and progression of gastric cancer [ 174 ]. Additionally, soluble factors produced by HCC cells promote neutrophil survival by increasing autophagy, subsequently facilitating cancer cell metastasis [ 175 ]. Conversely, low expression levels of Beclin-1 in human neutrophils have been significantly correlated with upregulated PD-L1 levels in patients with pre-B acute lymphoblastic lymphoma [ 176 ]. In this context, Beclin-1 deficiency induces autophagy inhibition that suppresses CD8 + T cell function, illustrating a potential immunosuppressive mechanism [ 176 ]. In recent years, researchers have discovered that neutrophils can capture and kill pathogens by forming neutrophil extracellular trapping networks (NETs), a process known as NETosis [ 177 ]. Neutrophil autophagy is essential for NETs formation; inhibiting autophagy can impair NETosis and lead to neutrophil apoptosis [ 177 ]. Similarly, mTOR inhibitors can enhance the formation of neutrophil autophagosomes and facilitate the release of NETs [ 178 ]. Previous studies have shown that NETs can envelop and adhere to tumor cells, promoting tumor dissemination and metastasis [ 177 , 179 ]. Therefore, inhibiting autophagy and, consequently, NETs production emerges as a promising anti-tumor strategy.

Autophagy of NK cells

As innate immune cells, NK cells exert anti-tumor effects through three primary mechanisms: (1) direct cytotoxicity against tumor cells (2) cytokine production (3) antibody dependent cellular cytotoxicity [ 180 ]. Several studies have reported that the inhibition of autophagy (e.g., ATG5 and ATG7 deletion) induces mitochondrial damage and elevated ROS, leading to apoptosis in NK cells and a compromised innate immunity [ 181 , 182 ]. Further research shows that FOXO1 can induce autophagy by binding to ATG7 in an mTOR signal independent manner in NK cells, thereby promoting NK cell development [ 181 ]. Similarly, genetic deletion of TRPML1 in the lysosomes of NK cells inhibits autophagy, resulting in the accumulation of damaged mitochondria, increased ROS and decreased ATP, consequently damaging NK cells migration [ 183 ]. Furthermore, NK cells with autophagy defects show a significant reduction in the expression of critical cytokines such as IL-4 and IFN-γ, which are vital for immune responses [ 184 ].Overall, the current studies agree that autophagy is a positive regulator for NK cells in terms of their anti-tumor effects.

Autophagy of B cells

Although B cells are traditionally considered to have a primary function of producing antibodies and supporting immune memory, their role in tumor immunity is complex [ 185 ]. Autophagy is critical for the development and proliferation of B cells [ 186 ]. Studies have shown that while deletion of the ATG5 gene has minimal effects on B cell differentiation, it is essential for maintaining normal peripheral B cell counts, which is crucial for sustaining long-term autoimmune responses [ 186 ]. Memory B cells display elevated levels of autophagy, and the absence of ATG7 in B cells inhibited the occurrence of autophagy, resulting in desensitization of memory B cells [ 187 ]. Furthermore, the pro-oxidant adaptor p66SHC promoted B cell mitophagy by disrupting mitochondrial integrity and recruiting LC3-II, mediating the survival and differentiation of B cells [ 188 ].

In conclusion, the autophagy pathway is integral to the regulation of the immune response in tumors. Investigating the diverse roles of autophagy in tumor cells and immune cells may facilitate the identification of potential therapeutic targets, thereby offering new perspectives for advancing anti-tumor immunity and refining immunotherapeutic approaches.

Advances in targeting autophagy in clinical trials of tumor immunotherapy

Given the important role of autophagy in modulating immune responses, several clinical trials have been initiated to explore the activation of anti-tumor immunity by targeting autophagy. Currently, CQ and hydroxychloroquine (HCQ) are the most frequently utilized autophagy inhibitors in clinical settings. Owing to its minimal side effects and favorable dosing profile, HCQ is often selected as a candidate drug for clinical trials [ 189 ]. Consequently, international clinical trials examining the combination of HCQ with immunosuppressants for the treatment of various solid tumors are currently underway; however, preliminary results have yet to be disclosed. Moreover, a phase III trial found that a multi-targeted receptor tyrosine kinase inhibitor Sunitinib can induce p62-mediated PD-L1 autophagy degradation, thus facilitating antitumor immunity in breast cancer patients with metastasis [ 55 ]. Induction and collection of tumor-derived autophagosomes from tumor cells into a novel anti-tumor vaccine (DRibbles) that can effectively activate naïve T cells by upregulating MHC-I on DCs. Preliminary results are now available from a clinical trial against DRibbles. The study showed that six patients received treatment with doxorubicin in conjunction with DRibbles, with only one patient exhibiting a tumor-specific immune response. Researchers have postulated that the limited immune response may be attributed to the advanced stage of the patients enrolled in the trial, which complicates disease management. Furthermore, the insufficient number of patients enrolled in the trial impeded the thorough evaluation of the vaccine's efficacy in tumors. The feasibility of the research plan was deemed low due to the extended preparation time required for DRibbles in advanced-stage patients [ 190 ]. The clinical translation of autophagy targeting to enhance immunotherapy is expected to be a protracted and challenging endeavor, with numerous unresolved issues that demand immediate attention (Table 3 ). Table 3 The ongoing clinical trials about the combinations of immunotherapy with autophagy targeted drugs NCT Number Cancer Types Interventions Sponsor Phases Enrollment NCT04841148 Breast Cancer HCQ/Avelumab + Palbociclib Abramson Cancer Center at Penn Medicine II 96 NCT04464759 Melanoma Nivolumab/Ipilimumab + HCQ Ravi Amaravadi, MD I/II 94 NCT04787991 Metastatic Pancreatic Adenocarcinoma HCQ/Nivolumab + Ipilimumab + Nab-paclitaxel/Gemcitabine Parker Institute for Cancer Immunotherapy I 45 NCT05448677 HCC Ezurpimtrostat + Atezolizumab/ Bevacizumab University Hospital, Grenoble II 196 NCT03344172 Pancreatic Cancer Resectable Gemcitabine + Nab-Paclitaxel + hydroxychloroquine + Avelumab Nathan Bahary, MD II 32 NCT01550367 Metastatic Renal Cell Carcinoma Hydroxychloroquine + IL-2 Leonard Appleman I/II 30 NCT04214418 Gastric cancer Cobimetinib + Hydroxychloroquine + Atezolizumab Columbia University I/II 175 NCT05576896 Stage IV CRC Hydroxychloroquine + Encorafenib + Cetuximab/Panitumumab Northwestern University II 43 NCT00850785 NSCLC DRibble vaccine Providence Health & Services I 6 NCT01909752 NSCLC Cyclophosphamide + DRibble vaccine + HPV vaccine + Imiquimod/GM-CSF UbiVac II 12 NCT03057340 NSCLC Dribble vaccine Second Affiliated Hospital, School of Medicine, Zhejiang University I 30 NCT02234921 Adenocarcinoma of the Prostate Cyclophosphamide + DRibble Vaccine + HPV Vaccine + Imiquimod UbiVac I 3 NCT00798135 Breast Neoplasms (Metastasis) Itraconazole Indiana University NA 13 * NSCLC non-small cell lung cancer; HCC hepatocellular carcinoma; CRC colorectal cancer; HCQ hydroxychloroquine; CSF colony stimulating factor

Conclusion

Autophagy plays an important and complex role in regulating tumor immunity, and its activation or inhibition is shown to counteract the activation or inhibition of tumor immunity. The bidirectional role of autophagy in regulating tumor immunity is cell- and microenvironment-dependent. For example, autophagy in NK cells promotes anti-tumor immunity, whereas autophagy in tumor cells may suppress anti-tumor immunity by inhibiting antigen presentation. Currently, most cellular and animal experiments targeting autophagy in combination with immunotherapy have shown that combination therapy is more effective than monotherapy. This underscores the promising applications of combination strategies, although significant challenges remain. The same therapeutic strategy may yield diametrically opposed outcomes due to the varying roles of autophagy in different tumors, the diverse signaling that regulating autophagy, and the distinct effects of autophagy on various immune cell subpopulations. Additionally, the interplay between autophagy and the immune system is characterized by both positive and negative feedback mechanisms. This raises the question: does immunity influence autophagy, and how does autophagy in turn affect immune function? Key considerations for the optimal utilization of autophagy to enhance future immunotherapy strategies include: whether the sensitizing impact of autophagy inhibitors or activators are tumor-specific or stage-specific; which components of the autophagic signaling pathway are targeted; the specific cell types selected for autophagy disruption; the optimal timing for interfering with autophagy—whether before, during, or after immunotherapy; the most effective dosages of autophagy inhibitors or activators when used in combination with immunotherapy; the duration of treatment with autophagy inhibitors or activators; and the potential clinical side effects associated with autophagy inhibition.

To address these questions, we must deepen our understanding of how autophagy systematically regulates tumor cells, immune cells, and stromal cells to influence tumor progression. Deciphering these mechanisms and developing temporally and spatially targeted strategies for autophagy flux regulation will be the key to effectively targeting autophagy in improving immunotherapeutic sensitivity and anti-tumor efficacy.

Abbreviations

Tumor immune microenvironment

Programmed cell death ligand 1

Programmed cell death protein 1

Cytotoxic T-lymphocyte-associated protein 4

Dendritic cells

Natural killer

Major histocompatibility complex

Non-small cell lung cancer

Regulatory T cells

Myeloid-derived suppressor cells

Hepatocellular carcinoma

Colorectal cancer

Immunogenic cell death

Chloroquine

MHC class I

MHC class II

Colony stimulating factor

Tumor-associated macrophages

Damage-associated molecular patterns

High mobility group box 1

Helper T cells

Monocytic MDSCs

Granulocytic MDSCs

Neutrophil extracellular trapping networks

Hydroxychloroquine

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Authors’ contributions

H.W. and Yl.S. contributed to the study design. P.S. Xj.Y. contributed to the implementation, manuscript discussion and critical revision. H.W., Yl.S., Zy.X., Xy.J. and Ms.X. collected and interpreted the data. All the authors read and approved the final manuscript.

Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 32300753).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

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