==== Front MedComm (2020) MedComm (2020) 10.1002/(ISSN)2688-2663 MCO2 MedComm 2688-2663 John Wiley and Sons Inc. Hoboken 10.1002/mco2.311 MCO2311 Review Reviews Modulation of the immunity and inflammation by autophagy GAN et al. Gan Ting 1 2 3 4 Qu Shu 1 2 3 4 Zhang Hong 1 2 3 4 Zhou Xu‐jie 1 2 3 4 zhouxujie@bjmu.edu.cn 1 Renal Division Peking University First Hospital Beijing China 2 Peking University Institute of Nephrology Beijing China 3 Key Laboratory of Renal Disease Ministry of Health of China Beijing China 4 Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University) Ministry of Education Beijing China * Correspondence Xu‐jie Zhou, Renal Division, Peking University First Hospital, No. 8, Xishiku Street, Xicheng District, Beijing, China. Email: zhouxujie@bjmu.edu.cn 02 7 2023 8 2023 4 4 10.1002/mco2.v4.4 e31112 5 2023 10 12 2022 26 5 2023 © 2023 The Authors. MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd. https://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Abstract Autophagy, a highly conserved cellular self‐degradation pathway, has emerged with novel roles in the realms of immunity and inflammation. Genome‐wide association studies have unveiled a correlation between genetic variations in autophagy‐related genes and heightened susceptibility to autoimmune and inflammatory diseases. Subsequently, substantial progress has been made in unraveling the intricate involvement of autophagy in immunity and inflammation through functional studies. The autophagy pathway plays a crucial role in both innate and adaptive immunity, encompassing various key functions such as pathogen clearance, antigen processing and presentation, cytokine production, and lymphocyte differentiation and survival. Recent research has identified novel approaches in which the autophagy pathway and its associated proteins modulate the immune response, including noncanonical autophagy. This review provides an overview of the latest advancements in understanding the regulation of immunity and inflammation through autophagy. It summarizes the genetic associations between variants in autophagy‐related genes and a range of autoimmune and inflammatory diseases, while also examining studies utilizing transgenic animal models to uncover the in vivo functions of autophagy. Furthermore, the review delves into the mechanisms by which autophagy dysregulation contributes to the development of three common autoimmune and inflammatory diseases and highlights the potential for autophagy‐targeted therapies. This review presents an overview of the autophagy machinery and summarizes the roles of autophagy and autophagy proteins in regulating immunity and inflammation. The authors discuss how dysregulation of autophagy contributes to the pathogenesis of three common autoimmune and inflammatory diseases and emphasize autophagy as a promising therapeutic target. autophagy immunity inflammation autoimmune diseases pathogenesis National Science Foundation of China 10.13039/501100001809 82022010 82131430172 81970613 Beijing Natural Science Foundation 10.13039/501100004826 Z190023 Academy of Medical Sciences‐Newton Advanced FellowshipNAFR13\1033 King's College London‐Peking University Health Science Center Joint Institute for Medical ResearchBMU2021KCL004 Fok Ying Tung Education Foundation 10.13039/501100010261 171030 Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences2019‐I2M‐5‐046 2020‐JKCS‐009 National High Level Hospital Clinical Research Funding (Interdisciplinary Clinical Research Project of Peking University First Hospital)2022CR41 source-schema-version-number2.0 cover-dateAugust 2023 details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.3.0 mode:remove_FC converted:02.07.2023 Gan T , Qu S , Zhang H , Zhou X . Modulation of the immunity and inflammation by autophagy. MedComm. 2023;4 :e311. 10.1002/mco2.311 ==== Body pmc1 INTRODUCTION Autophagy is a conserved process that facilitates the degradation and recycling of various cellular components by delivering them to lysosomes. 1 Originally known as a mechanism for ensuring the quality of organelles and proteins, autophagy has also gained recognition as a means of survival under circumstances of limited energy or nutrient availability. Recent studies have expanded our knowledge regarding autophagy and revealed its role in immunity and inflammation. The emergence of this fresh outlook has been partly propelled by the linkages established between genetic variations in genes associated with autophagy and heightened vulnerability to autoimmune and inflammatory disorders. Following the discovery of the Thr300Ala variant in ATG16L1 as a genetic predisposition for Crohn's disease (CD) via genome‐wide association studies (GWAS), 2 , 3 several research teams generated transgenic animal models to illustrate the crucial involvement of autophagy in maintaining intestinal epithelial homeostasis and defending against infections. 4 , 5 , 6 , 7 , 8 , 9 , 10 Moreover, associations have been established between mutations in different genes related to autophagy and diverse autoimmune and inflammatory conditions, 11 , 12 , 13 , 14 , 15 fueling significant enthusiasm in understanding the contribution of autophagy to the pathogenesis of these diseases. Considerable progress has been achieved in unraveling the functional aspects of autophagy in immunity and inflammation through the utilization of both in vitro and in vivo models. 16 , 17 By executing diverse functions such as pathogen clearance, antigen processing and presentation, cytokine production, as well as lymphocyte differentiation and survival, autophagy serves as a crucial bridge between the innate and adaptive immune systems. However, our comprehension of how autophagy influences immunity and inflammation is far from complete. Emerging studies have uncovered novel methods by which the autophagy pathway and autophagy proteins regulate immune responses, such as noncanonical autophagy. 18 , 19 This review highlights recent advancements in understanding the impact of autophagy on the regulation of immune responses and inflammatory processes. It presents the genetic links between variants in autophagy‐related genes (ATGs) and a range of autoimmune and inflammatory diseases. Additionally, it explores the in vivo function of autophagy through the utilization of transgenic animal models. Furthermore, this review delves into the underlying mechanisms by which autophagy dysregulation contributes to the pathogenesis of three prevalent autoimmune and inflammatory disorders: inflammatory bowel diseases (IBD), systemic lupus erythematosus (SLE), and multiple sclerosis (MS). Finally, it summarizes the findings of clinical trials using autophagy‐targeted drugs and biological agents and explores the prospects of therapies aimed at modulating autophagy. 2 AUTOPHAGY AND RELATED MOLECULAR PATHWAYS Autophagy is a conservative mechanism of self‐degradation, which transports cellular materials to lysosomes for decomposition. The process of autophagy encompasses three distinct mechanisms: macroautophagy, microautophagy, and chaperone‐mediated autophagy, each employing unique strategies for transporting cargo to the lysosome. 20 , 21 Unless otherwise specified in this review, the extensively investigated form of autophagy, macroautophagy, will be predominantly referred to as such. The regulation of autophagy involves two key kinases: adenosine monophosphate (AMP) ‐activated protein kinase (AMPK), which monitors energy levels, and mammalian target of rapamycin (mTOR), which detects nutrient availability. 22 The activation of AMPK, which is essential for regulating cellular energy metabolism, is triggered by alterations in energy status, such as an elevation in the AMP/ATP ratio or reduced glucose levels. 23 Conversely, mTOR serves as a prominent controller of cell growth and protein synthesis, and its activation is induced by abundant nutrient availability, normoxic conditions, and elevated levels of growth factors. 22 AMPK enhances autophagy by promoting the phosphorylation of ULK1, while mTOR inhibits autophagy by preventing ULK1 activation. 24 Autophagy progresses through distinct stages encompassing autophagy initiation, autophagosome nucleation, autophagosome elongation and closure, as well as autophagosome fusion with lysosomes. 21 The progression of this process is facilitated by a group of proteins encoded by ATG, as depicted in Figure 1. The intricate molecular mechanisms underlying autophagy are extensively discussed in other expert reviews. 25 FIGURE 1 The process and molecular mechanism of autophagy. †Autophagy proceeds through a series of sequential phases, including autophagy initiation, nucleation of the autophagosome, elongation and closure of the autophagosome, and fusion of the autophagosome with lysosome. The process is mediated by a set of proteins encoded by autophagy‐related (ATG) genes. Although macro‐, micro‐, and chaperone‐mediated autophagy are all considered to be genuine forms of autophagy, as they transport cytoplasmic materials to lysosomes, 26 recent research has revealed noncanonical autophagy pathways. These pathways are called noncanonical autophagy because they use distinct molecular pathways to process and conjugate microtubule‐associated protein light chain 3 (LC3). 27 Noncanonical autophagy processes may specifically contribute to pathogen removal, surface molecule internalization, secretion/exocytosis, and phagocytosis. 26 An exemplary instance is LC3‐associated phagocytosis (LAP), 18 where specific constituents of the canonical autophagy machinery are engaged to facilitate the binding of LC3 to phagosomes with a single membrane. 28 , 29 LAP can be triggered by various surface receptors such as pattern recognition receptors (PRRs), immunoglobulin (Ig) receptors, and phosphatidylserine (PtdSer) receptors, which will be further discussed below. 3 AUTOPHAGY IN IMMUNITY AND INFLAMMATION Although initially discovered for its role in degrading unwanted or damaged cytoplasmic material to maintain cellular homeostasis, recent studies also suggest that autophagy has broader functions in immunity and inflammation. 30 Autophagy contributes to innate immunity by assisting in pathogen clearance and inflammation regulation. Two autophagy‐associated pathways, xenophagy and LAP, are utilized by innate immune phagocytes to promote degradation of microbes within lysosomes. 31 Xenophagy, a typical type of autophagy, selectively captures intracellular pathogens and those in damaged intracellular vesicles into double‐membrane autophagosomes, which then undergoes degradation via the lysosomal pathway through autophagy. 32 LAP, on the other hand, collaborates with canonical autophagy in cellular defense. Pathogenic microorganisms have been observed within LAP‐targeted, single‐membrane phagosomes, promoting phago‐lysosomal fusion and leading to enhanced microbial killing. Studies have revealed that the absence of ATGs, such as Atg5, renders mice more susceptible to infections and disrupts normal inflammatory responses. 33 Autophagy is therefore critical to balance inflammatory response by timely removing exogenous and endogenous sources of inflammatory signals, such as microbes, damaged organelles, and aggregates. One of the major functions of the autophagy mechanism in regulating inflammation is to suppress inflammasome activation. The inflammasome functions as a receptor and sensor within the innate immune system, governing the activation of caspase‐1 and triggering the proteolytic cleavage of pro‐IL‐1β and pro‐IL‐18. This activation occurs upon the recognition of pathogen‐associated molecular patterns (PAMPs) or damage‐associated molecular patterns (DAMPs). 34 , 35 By eliminating endogenous inflammasome activators, such as damaged mitochondrial‐derived DAMPs, autophagy demonstrates its ability to dampen inflammasome activation. 36 Additionally, autophagy can directly target inflammasome components and eliminate them by autophagic degradation. Autophagy plays an additional pivotal role in regulating inflammation by inhibiting the generation of type I interferon (IFN), which is mediated by cyclic guanosine monophosphate (GMP) –AMP synthase (cGAS) and stimulator of interferon genes (STING). The cGAS–STING pathway consists of the dsDNA/DNA hydrolysate sensor cGAS and the STING. 37 Upon detection of dsDNA/dsRNA from exogenous and endogenous sources, cGAS catalyzes the production of cyclic GMP–AMP (cGAMP) using ATP and GTP. Subsequently, cGAMP binds to the active site of STING, initiating downstream signaling pathways and promoting the synthesis of type I IFN. Emerging evidence indicates that autophagy plays a role in mitigating excessive inflammation through downregulating the activation of the cGAS–STING pathway. The interaction between the autophagy‐related protein BECN1 and the cGAS DNA sensor has been identified as a key mechanism. This interaction promotes the degradation of cytoplasmic pathogen DNA through autophagy, effectively limiting the excessive production of inflammatory cytokines. 38 , 39 The deficiency of the ATG Atg9a has been shown to markedly increase the assembly of STING, resulting in aberrant activation of the innate immune response. 40 Autophagic degradation of STING can attenuate STING‐directed type I IFN signaling activity. For instance, a newly identified autophagy receptor CCDC50 delivers K63‐polyubiquitinated STING to the autolysosome for degradation. 41 Furthermore, it has been observed that the small‐molecule chaperone UXT facilitates the autophagic degradation of STING1 by promoting its interaction with SQSTM1, a process that contributes to the regulation of STING1 levels. 19 , 42 These findings emphasize the essential role of autophagy in modulating the activation of STING to maintain immune homeostasis. Autophagy plays a pivotal role in bridging innate and adaptive immunity by facilitating antigen presentation. Recent studies have provided emerging evidence that autophagy plays a facilitating role in the presentation of antigens on major histocompatibility complex (MHC) class II molecules. 43 Two autophagy‐related mechanisms exist in antigen‐presenting cells (APCs) for the presentation of antigens on MHC class II molecules. The first mechanism involves the capture and delivery of extracellular antigens to the autophagosome, where MHC class II molecules are subsequently recruited to the phagolysosome. This process generates immunogenic peptides that engage with CD4+ T cells. The second mechanism entails the utilization of noncanonical autophagy LAP, wherein specific receptors like Toll‐like receptors (TLRs) recognize the cargo, resulting in the conjugation of LC3 to single‐membrane phagosomes and the subsequent formation of LAPosomes. 19 The fusion between LAPosomes and lysosomes facilitates the efficient degradation of cargo and the generation of fragments that can be loaded onto MHC class II molecules, thereby triggering the activation of CD4+ T cells. Furthermore, autophagy plays a role in directing cytosolic proteins for degradation in lysosomes, thereby enhancing the presentation of intracellular antigens on MHC class II molecules and facilitating robust CD4+ T cell responses. It is also crucial to consider the role of autophagy in the context of endogenous MHC class II loading during thymic selection, as it plays a vital role in shaping the T cell repertoire. 44 Considerable autophagic activity is observed in thymic epithelial cells (TECs), which plays a crucial role in the establishment of self‐tolerance in CD4+ T cells by presenting self‐antigens on MHC class II molecules during their development. 16 Altered selection of specific MHC‐II restricted T cells and the development of multi‐organ inflammation are observed in TECs lacking Atg5. 45 , 46 These findings highlight the crucial involvement of autophagy in inducing tolerance during the development of the T cell repertoire. 47 In addition to its role in antigen presentation, autophagy also plays a crucial role in modulating the development and maintenance of immune cells, thus contributing to adaptive immunity. For instance, targeted deletion of Atg5 in distinct subsets of immune cells in murine models has been shown to result in notable impairments in various aspects of immune function, such as compromised B lymphocyte maturation, impaired differentiation of plasma cells, diminished T cell survival, and reduced T cell proliferation. 48 , 49 , 50 In addition to its aforementioned immunomodulatory functions, autophagy's role in onco‐immunology is also increasingly recognized. The involvement of autophagy in tumor development is influenced by multiple variables, such as the specific tumor subtype, stage of progression, and the characteristics of the tumor microenvironment. Autophagy plays a critical role in maintaining homeostasis, activating, differentiating, and promoting the survival of immune cells, which in turn can have both promotive and inhibitory effects on tumor development. Thus, autophagy functions as a double‐edged sword in the context of tumorigenesis. Since the topic of autophagy and tumor immunity has been covered comprehensively in recent reviews, 51 , 52 , 53 , 54 we will focus on a few studies of notable significance to discuss the impact of autophagy on tumor immunity. To begin, autophagy plays a role in regulating antigen processing and presentation within tumor cells. MHC class I (MHC‐I) molecules are crucial for antitumor adaptive immunity as they facilitate the presentation of endogenous antigens to CD8+ T cells. 55 Impaired MHC‐I expression in tumor cells can hinder antigen presentation and enable immune evasion. Recent investigations have suggested that autophagy may contribute to immune evasion in pancreatic cancer by participating in the degradation of MHC‐I molecules. 56 In pancreatic ductal adenocarcinoma (PDAC) cells, lysosomes were found to be enriched with MHC‐I, while its expression on the cell surface was reduced. Researchers discovered that the autophagy cargo receptor NBR1 facilitates the transport of MHC‐I molecules to lysosomes for degradation via an autophagy‐dependent pathway. 56 Inhibition of autophagy restores surface MHC‐I levels, leading to increased antigen presentation, enhanced proliferation and activation of CD8+ T cells, and augmented tumor cell elimination. Additionally, autophagy inhibition through ULK1 targeting has been demonstrated to overcome impaired antigen presentation and restore antitumor immunity in lung cancer with LKB1 mutation. 57 Therefore, interfering with autophagy in tumor cells may provide an effective way to promote an antitumor T‐cell response. Furthermore, recent discoveries have highlighted the involvement of LAP in the engulfment of apoptotic tumor cells. During tumor progression, the heightened rate of cell proliferation often coincides with an elevated incidence of cell death. Moreover, anticancer treatments can induce cell death in tumors. Therefore, the presence of numerous dying or dead cells in the tumor microenvironment provides an abundant supply of pre‐existing substrates for professional phagocytic cells. 58 LAP utilizes autophagy machinery components to facilitate optimal maturation of phagocytic cells and degradation of ingested cargo. LAP can promote clearance of dying or dead cells by interacting with the surface receptor T‐cell Ig mucin protein 4 (TIM‐4) on macrophages. 59 New research findings suggest that LAP plays a significant role in the engulfment of dying and deceased cells by bone marrow macrophages within the microenvironment of acute myeloid leukemia (AML). 60 Researchers found that apoptotic bodies from AML cells were taken up by bone marrow macrophages via LAP, followed by mtDNA stimulation of STING to enhance phagocytosis and inhibit AML cell growth. 59 Therefore, AML disease progression is expedited in mice with deficiencies in LAP. However, this macrophage function associated with AML contrasts with the immunosuppressive role of LAP in solid tumors. Researchers have noted that in mice with solid tumors like melanoma and lung cancer, LAP present in myeloid cells facilitated the growth of the tumors. 61 At the mechanistic level, LAP serves as a regulatory mechanism in steering the polarization of tumor‐associated macrophages (TAMs) toward an immunosuppressive state, as demonstrated by recent studies. 61 Additionally, after engulfing apoptotic tumor cells, LAP inhibits the production of type I IFN in TAMs. Therefore, it suppresses T cell function and enhances tumor tolerance. These findings emphasize that the effect of LAP is contingent on various factors, including cancer type and stage. Further study is warranted to shed light on the underlying reasons for these discrepancies. 4 AUTOPHAGY IN AUTOIMMUNE AND INFLAMMATORY DISEASES The association between mutations in ATGs and heightened susceptibility to autoimmune and inflammatory diseases has piqued interest in the involvement of autophagy in disease mechanisms. Nevertheless, as indicated in Table 1, the majority of genetic variations are found within noncoding regions, with only a limited portion of the predicted heritability attributable to functional variations. As a result, it is challenging to translate genetic variation information into mechanistic insights. Nonetheless, transgenic animals are useful tools for improving our understanding of disease etiology. In particular, when animal models with functional variations are shown to alter gene functions, it can provide strong evidence for the gene's contribution to disease pathogenesis. The subsequent sections will focus on three common autoimmune and inflammatory diseases and examine how autophagy dysregulation contributes to disease development, primarily drawing from evidence obtained through transgenic animal models. TABLE 1 The list of variants in autophagy‐related genes associated with the susceptibility to several autoimmune and inflammatory diseases. Disease Gene Chromosome SNP Reference Alternate Functional annotation OR p Value Study strategy References IBD ATG16L1 2 rs2241880 (T300A) A G missense_variant 1.32 3.00E−06 GWAS & fine‐mapping 62 1.45 1.00E−13 GWAS & fine‐mapping 63 1.32 1.00E−12 GWAS & fine‐mapping 64 rs3828309 A G intron_variant 1.25 2.00E−32 GWAS meta‐analysis 65 rs12994997 G A intron_variant 1.23 4.00E−70 GWAS meta‐analysis 66 rs10210302 C T intron_variant 1.19 5.00E−14 GWAS & fine‐mapping 67 IRGM 5 rs11747270 A G intron_variant 1.33 3.00E−16 GWAS meta‐analysis 65 rs1000113 C T intron_variant 1.54 3.00E−07 GWAS & fine‐mapping 67 rs11741861 A G intron_variant 1.33 6.00E−44 GWAS meta‐analysis 68 rs13361189 T C intergenic_variant 1.38 2.00E−10 Candidate gene 69 rs7714584 A G intron_variant 1.37 8.00E−19 GWAS meta‐analysis 70 ATG16L2 11 rs11235604 C T missense_variant 1.61 2.44E−12 GWAS & fine‐mapping 71 LRRK2 12 rs11175593 C T non_coding_transcript_exon_variant 1.54 3.00E−10 GWAS meta‐analysis 65 rs4768236 C A intron_variant 1.12 4.00E−21 GWAS meta‐analysis 68 ULK1 12 rs12303764 T G intron_variant 1.32 2.00E−04 Candidate gene 72 SLE ATG7 3 rs11706903 C A intron_variant 1.26 1.12E−04 GWAS pathway analysis 73 IRGM 5 rs10065172 C T synonymous_variant 1.15 1.50E−02 GWAS pathway analysis 73 rs13361189 T C 5' of IRGM 1.13 3.00E−02 GWAS pathway analysis 73 ATG5 6 rs548234 C T 3' of ATG5 1.25 5.00E−12 GWAS & fine‐mapping 11 rs6937876 G A 3' of ATG5 1.70 1.40E−02 Candidate gene 73 rs2245214 C G intron_variant 1.15 1.20E−05 Candidate gene 74 ATG16L2 11 rs11235604 C T missense_variant 0.76 1.90E−09 GWAS & fine‐mapping 12 DRAM1 12 rs4622329 G A intron_variant 1.12 4.00E−15 GWAS meta‐analysis 13 1.19 9.00E−12 GWAS meta‐analysis 75 CLEC16A 16 rs34361002 T TAA intron_variant 1.14 1.00E−17 GWAS meta‐analysis 13 rs12599402 T C intron_variant 1.28 5.00E−07 GWAS meta‐analysis 75 rs7200786 A G intron_variant 1.15 2.00E−08 GWAS meta‐analysis 76 rs9652601 G A intron_variant 1.21 7.00E−17 GWAS meta‐analysis 76 1.17 4.00E−07 GWAS meta‐analysis 77 1.19 6.00E−13 GWAS meta‐analysis 78 rs2041670 G A intron_variant 1.18 2.00E−16 GWAS meta‐analysis 78 rs8054198 C T TF_binding_site_variant 2.78 2.00E−08 GWAS meta‐analysis 78 MAP1LC3B 16 rs933717 T C intron_variant 0.13 2.36E−10 GWAS pathway analysis 79 MTMR3 22 rs9983 G A 3_prime_UTR_variant 1.61 2.07E−03 GWAS shared genetics 80 MS CALCOCO2 17 rs550510 G A missense_variant 0.65 7.00E−03 Candidate gene 81 RA ATG16L1 2 rs2241880 A G missense_variant 1.32 2.00E−02 Candidate gene 82 ATG5 6 rs62422878 C T intron_variant 1.11 4.00E−09 GWAS meta‐analysis 14 rs9372120 T G intron_variant 0.11 1.00E−07 GWAS meta‐analysis 15 1.11 8.00E−10 GWAS meta‐analysis 83 UVRAG 11 rs7111334 C T intron_variant 0.25 1.50E−02 Candidate gene 84 GABARAPL3 15 rs6496667 C A 5' of GABARAPL3 1.09 1.00E−06 GWAS meta‐analysis 85 Psoriasis ATG16L1 2 rs13005285 T G intron_variant 1.32 2.40E−02 Candidate gene 86 Data were collected from GWAS catalog database (https://www.ebi.ac.uk/gwas/); IBD, inflammatory bowel diseases; SLE, systemic lupus erythematosus; MS, multiple sclerosis; RA, rheumatoid arthritis; GWAS, genome‐wide association study; SNP, single‐nucleotide polymorphism; OR, odds ratio. John Wiley & Sons, Ltd. 4.1 Inflammatory bowel diseases IBD, encompassing CD and ulcerative colitis, manifests as a chronic gastrointestinal disorder marked by severe inflammation and mucosal damage. 87 The exact mechanism of IBD remains unclear, but potential causes such as environmental factors, infectious agents, and genetic susceptibility have been proposed. 88 Many genetic variants in ATG genes have been identified as influential factors in the onset of IBD and one of these variants is a missense mutation (rs2241880, Thr300Ala) located in the autophagy gene ATG16L1. This discovery has generated significant interest in unraveling the role of autophagy in the context of IBD. Moreover, GWAS have revealed additional single‐nucleotide polymorphisms (SNPs) in ATG genes that exhibit a strong association with IBD, as shown in Table 1. Considering that most of the evidence linking autophagy‐related genetic variants to IBD is derived from functional studies utilizing the ATG16L1 T300A variant, our discussion will focus primarily on ATG16L1, supplemented by other ATGs. The T300A variant (Thr300Ala) causes the substitution of the evolutionarily conserved polar threonine residue at position 300 of the WD repeat domain in ATG16L1 with a nonpolar alanine. During the process of autophagosome formation, the ATG16L1 protein engages in interactions with the ATG12–ATG5 conjugate, leading to the formation of a large molecular complex. This complex facilitates the lipidation of LC3/ATG8, thereby contributing to autophagosome development. 89 , 90 Mice with functional defects in Atg16l1 display dysregulated autophagy and intestinal homeostasis, and the relevant mechanisms are summarized in Figure 2. FIGURE 2 The roles of autophagy deficiency in pathogenesis of inflammatory bowel diseases (IBD). †Defective autophagy can affect gut microbiota composition, disrupt intestinal epithelial homeostasis, and amplify intestinal inflammation in IBD. 4.1.1 Intestinal epithelial homeostasis In a healthy state, the intestinal epithelial cells (IECs) establish a strong mucosal barrier capable of withstanding intestinal pathogens. Additionally, specialized epithelial cells, including Paneth and goblet cells, secrete defensins and mucus to limit bacterial adhesion and infiltration. 91 However, patients with IBD often exhibit defects in maintaining mucosal barrier stability, which leads to dysregulated mucosal immune responses to gut microbiota. Xenophagy is essential for eliminating intracellular pathogens, and autophagy‐associated risk variants have been linked to defective autophagy and impaired intracellular bacterial clearance. 92 Conway et al. 4 generated mice lacking Atg16l1 in epithelial cells and found that autophagy‐deficient mice had systemic translocation of bacteria and an exaggerated inflammatory response compared with their wild‐type counterparts. Under normal conditions, autophagosomes can engulf invaded S Typhimurium in IECs. However, mice with Atg16l1 deletion in IECs showed cell‐specific disruptions of autophagy and failed to control the spread of intestinal pathogens. In addition, these mice displayed abnormal morphology of Paneth cells, specialized epithelial cells that play a crucial role in the secretion of antimicrobial peptides. 93 , 94 In fact, IECs deficient in other ATGs, such as Irgm1 95 and Atg4b, 96 also showed marked Paneth cell alterations. Moreover, autophagy dysfunction in Atg16l1 T300A/T300A mice caused a defect in mucin secretion in their goblet cells. 5 Thus, impaired autophagy may compromise the release of antimicrobial peptides and mucin, leading to heightened vulnerability of the intestinal epithelial barrier to microbial infections. These observations underscore the crucial role of autophagy in preserving the equilibrium of the intestinal immune system through efficient elimination of harmful pathogens in the gut. 4.1.2 Inflammatory immune response IBD are chronic gastrointestinal inflammatory conditions, and autophagy has been underscored in recent research as a vital mechanism for regulating inflammatory responses. 6 , 97 Inflammasomes are typically activated upon stimulation by PAMPs or DAMPs to safeguard host cells against microbial infections. However, prolonged hyperactivation of inflammasomes can lead to excessive cytokine production and severe inflammatory diseases, including IBD. Therefore, precise control of inflammasome activation is indispensable in upholding intestinal equilibrium. Autophagy functions as an innate cellular defense mechanism by capturing the invaded pathogens, thereby preventing the recognition of PRRs and downstream inflammasome signaling. Autophagy defects have been reported to cause excessive inflammasome activation and abnormal inflammation. Saitoh et al. 7 showed that Atg16l1‐deficient macrophages exhibited heightened production of the proinflammatory cytokines IL‐1β and IL‐18 upon stimulation with lipopolysaccharide, owing to the activation of caspase‐1. 98 Additionally, mice harboring the Atg16l1 T300A variant, introduced via knock‐in, exhibited defective antibacterial autophagy and an increased cytokine response. 8 , 9 This phenomenon arises due to the increased susceptibility of the variant Atg16L1 T300A protein to cleavage by caspase 3 and caspase 7, as compared with the wild‐type protein. Consequently, this cleavage event results in reduced levels of functional ATG16L1 and perturbed cytokine signaling pathways. On the other hand, elevated inflammatory cytokines would accelerate the apoptosis of autophagy‐deficient IECs, resulting in impaired barrier function and exacerbated pathology. 10 Autophagy in the epithelium has been shown to reduce TNF‐induced apoptosis and limit intestinal inflammation. Therefore, functional autophagy is crucial for tightly regulating intestinal inflammation. 4.1.3 Gut microbiota The gut microbiota comprises trillions of bacteria inhabiting the mammalian intestinal lumen, and their interaction with the host is essential for maintaining physiological metabolism and intestinal immune equilibrium. The importance of autophagy in regulating the gut microbiota has been underscored by recent investigations. By eliminating intracellular pathogens, autophagy restricts the replication and dissemination of pathogenic microorganisms. In addition, autophagy helps regulate the gut microbiota composition by maintaining mucosal barrier stability. It is involved in secreting antimicrobial peptides and mucus into the intestinal lumen, which safeguards against pathogen invasion and infection. Dysfunctional autophagy has been associated with dysbiosis of the gut microbiota, which heightens the susceptibility to developing IBD. 99 Specifically, mice with gut‐specific Atg5 knockout display an altered gut microbiota composition and structure, characterized by an upsurge of proinflammatory bacteria and a decrease in alpha diversity. 100 , 101 Mice specifically lacking Atg7 in colonic epithelial cells also exhibit comparable outcomes. 102 Additionally, mice carrying the Atg16l1 T300A/T300A mutation exhibit an altered gut microbiota composition, characterized by a notable increase in the prevalence of bacteria linked to IBD, such as Ruminococcaceae. 5 , 103 These discoveries emphasize the significance of autophagy in maintaining gut microflora homeostasis. 4.2 Systemic lupus erythematosus SLE is distinguished by an excessive immune response and the breakdown of immune tolerance toward self‐antigens. 104 As shown in Table 1, the results of GWAS studies have yielded valuable insights into the link between genetic variations in ATGs and SLE susceptibility. 74 , 75 , 105 , 106 Further research involving cell biology and animal models has elucidated the functional mechanisms through which autophagy contributes to lupus pathogenesis. It is worth noting that LAP has also been shown to regulate the immune response in SLE (refer to Figure 3). FIGURE 3 The roles of autophagy dysregulation in the pathogenesis of systemic lupus erythematosus (SLE)/lupus nephritis (LN). †A deficiency in autophagy or noncanonical autophagy can result in defective processing and degradation of dead cells, overproduction of inflammatory cytokines, and autoreactive B cell activation, leading to increased proliferation and differentiation of B cell. Plasmacytoid dendritic cells (pDCs) can trigger the production of type I interferon by internalizing immune complexes via noncanonical autophagy. In the context of LN, autophagy can protect podocytes from injury, such as pathogenic autoantibodies, and interferon‐α. 4.2.1 The exposure of autoantigens One of the key factors in the development of SLE is the imbalance between the accumulation of material from dead cells and the disposal of apoptotic debris, which contributes to increased autoantigen exposure. Under normal circumstances, professional phagocytes like macrophages clear apoptotic debris, which remains sequestered from the immune system. However, impaired clearance of dead cell debris can activate nucleic acid recognition receptors, triggering the production of proinflammatory cytokines. Recent research has emphasized the crucial function of LAP, a distinct form of noncanonical autophagy, in the efficient removal of dead cells. 107 , 108 LAP facilitates phagosome maturation (i.e., LAPosomes) and the digestion of extracellular cargo using only a subset of autophagy machinery components. 109 Specifically, NADPH oxidase‐2 (NOX2) and Rubicon are indispensable components of LAP. Macrophages can trigger LAP and mediate subsequent efficient degradation of engulfed dead cells when the TIM4 receptor recognizes and engages with the “eat me” signal PtdSer expressed on dead cells. Uptake and degradation of dead cells are crucial for preventing an unwanted autoimmune response. In the absence of LAP, macrophages may have defects in the degradation of dead cells, resulting in an increase in the production of proinflammatory cytokines. 107 Additionally, mice with deficiencies in LAP pathway components, such as Cybb and Ncf1, displayed deficient uptake and degradation of necrotic material, increased production of inflammatory mediators, or exacerbated lupus. 110 , 111 4.2.2 The differentiation and survival of B cells One prominent characteristic of SLE is the generation of autoantibodies by self‐reactive B cells. 112 Extensive investigation underscores the importance of autophagy in the development of SLE by influencing B cell differentiation and the generation of autoantibodies. 113 , 114 In individuals with SLE, B cells exhibit elevated levels of autophagy compared with healthy individuals, and there exists a positive association between autophagosome density and disease activity as measured by the SLE Disease Activity Index (SLEDAI). 113 Deleting the negative autophagy regulator Rubcn has been found to provide survival advantages for SLE‐prone mice, including B6.Sle1.Yaa and MRL.Faslpr mice, by reducing autoantibody production and protecting them from renal disease. 115 Rubcn promotes autoimmunity in murine lupus by activating autoreactive B cells, promoting autoreactive germinal center reactions and plasmablast response. Autophagy also plays a critical role in the differentiation of plasma cells and the survival of memory B cells. 49 , 116 , 117 , 118 Deficiency in Atg5 or Atg7 impairs the terminal differentiation of B cells into plasma cells. 49 , 113 Moreover, autophagy is essential for maintaining the homeostasis of plasma cells, as these cells produce a large quantity of Igs, making them susceptible to severe endoplasmic reticulum stress, oxidative stress, and proteasome stress. 116 , 119 Plasma cells deficient in Atg5 are more vulnerable to cell death because they lack the protective effects provided by autophagy. 116 , 117 Modulating autophagy in B cells represents a potential strategy for controlling the production of autoantibodies, as the maintenance of memory cells is vital for long‐term humoral autoimmunity, and autophagy has been identified as a crucial player in this process. 118 4.2.3 Inflammatory immune response Exposure of the body to autoantigens containing nucleic acid can trigger an immune response, leading to the production of autoantibodies. The subsequent interaction between these autoantibodies and autoantigens can result in the formation of immune complexes, which possess the ability to initiate inflammation and cause tissue damage. Plasmacytoid dendritic cells (pDCs) take up immune complexes by binding to Fcγ receptors (FcγRs) and transport them to endosomal compartments where TLR7 and TLR9 are located. 120 This process leads to the overproduction of type I IFNs by pDCs. 121 , 122 LAP assists in transporting DNA‐immune complexes to TLR9, initiating signaling from FcγRs leading to type I IFN production. 123 Hayashi et al. 124 found that the recruitment of the IKKα complex to LC3‐containing LAPosomes is necessary for TLR9 signaling and type I IFN production. Autophagy is essential for the development of TLR7‐mediated SLE. 125 In a comparison of SLE development in Tlr7.1 transgenic mice with and without B cell‐specific Atg5 knockout, researchers observed that Tlr7.1 transgenic Atg5 knockout mice did not exhibit an IFN‐α signature in their serum. 125 This finding suggests that autophagy participates in the delivery of RNA ligands to the endosomes, thereby mediating the activation of autoreactive B cells. Additionally, dendritic cell‐specific Atg5 knockout mice also exhibited reduced IFNα and increased lifespan, 126 indicating the functional roles of autophagy in inflammation. 4.2.4 Response of kidney resident cells Lupus nephritis (LN) is a serious complication and a primary contributor to mortality among SLE patients. 127 While the exact function of autophagy in LN remains uncertain, its protective role in podocytes has been established. 22 Autophagosomes in podocytes have been observed in both MRLlpr/lpr mice suffering from nephritis and in renal biopsies from LN patients, signifying the activation and participation of autophagy in the development of LN. 128 When podocytes are exposed to pathogenic autoantibodies and IFN‐α, activated autophagy is negatively associated with indicators of podocyte injury such as podocyte apoptosis, podocin derangement, impaired cell migration, and increased cell permeability. Conversely, inhibition of autophagy worsens podocyte damage. It can be inferred from this evidence that autophagy is a crucial mechanism for protecting podocytes from injury. 128 , 129 The significance of autophagy and inflammasome signaling interactions in the regulation of podocyte injury has also been emphasized by recent studies. 129 , 130 , 131 Autophagy can capture and degrade inflammasomes via inflammasome ubiquitination, thereby controlling excessive inflammasome activation. 132 The expression of NLR family pyrin domain‐containing 3 (NLRP3) is significantly increased in the podocytes of patients with LN, and this upregulation is linked to podocyte injury. 129 In an intervention study, the augmentation of autophagy has been discovered to mitigate podocyte injury through the elimination of the NLRP3 inflammasome, whereas inhibition of autophagy can exacerbate podocyte injury. These results indicate the unique value of autophagy of the kidney resident cells in protecting against LN. 4.3 Multiple sclerosis MS is a disorder that impacts the central nervous system (CNS) and is distinguished by inflammation and demyelination. 133 Recent genetic studies have discovered a variant of the autophagy receptor CALCOCO2/NDP52, which seems to be linked to autophagy and MS. 134 In addition, there is abnormal expression of ATG5 in both the blood and brain tissue of MS patients. 135 , 136 , 137 , 138 Researchers have utilized mice with autophagy gene knockouts to investigate the role of autophagy in the progression of MS (refer to Table 2). Current existing evidence suggests that the impact of autophagy on MS is multifaceted, with its effects being both advantageous and deleterious, contingent upon the specific cellular context (refer to Figure 4). TABLE 2 The phenotypes of mice with genetically modified autophagy in several autoimmune and inflammatory diseases models. Disease model Gene Strategy of gene editing Phenotype References IBD Atg16l1 Conditional deletion of Atg16l1 in the IECs Paneth cell abnormalities; a significant surge in inflammation accompanied by the dissemination of bacteria after infection with S typhimurium 4 Knock‐in T300A variant Goblet cells exhibited impaired granule exocytosis; an insufficient and disrupted mucus layer; diminished mucin secretion; aggravated inflammatory response in DSS‐induced colitis; microbiota dysbiosis 5 Conditional deletion of Atg16l1 in T cells Spontaneous intestinal inflammation 6 Knockout Atg16l1 Heightened IL‐1β production in response to LPS or endotoxin stimulation; highly susceptible to dextran sulphate sodium‐induced acute colitis 7 Knock‐in T300A variant Impaired elimination of pathogens; heightened inflammatory cytokine response 8 Knock‐in T300A variant Abnormal morphology of Paneth cells and goblet cells; increased IL‐1β production 9 Conditional deletion of Atg16l1 in the IECs Increased release of proinflammatory cytokines; enhanced apoptosis of intestinal epithelial cells 10 Knock‐in hypomorphic Atg16l1 Extraordinary abnormalities in Paneth cells 93 Atg5 Conditional deletion of Atg5 in the IECs Paneth cell and granule abnormalities 93 Irgm1 Knockout Irgm1 Significant changes in the positioning and morphology of Paneth cells; heightened acute inflammation after dextran sodium sulfate exposure 95 Atg4b Knockout Atg4b Malfunctions in Paneth cells; heightened vulnerability to colitis induced by DSS 96 Atg5 Conditional deletion of Atg5 in the IECs Paneth cell morphological abnormalities; significant disruption in the gut microbiota composition accompanied by a decrease in alpha diversity 100 Atg7 Conditional deletion of Atg7 in the colonic epithelial cell Aggravation of experimental colitis; diminished secretion of colonic mucins; abnormal microflora 102 SLE Atg5 Conditional deletion of Atg5 in B cell Diminished antibody responses in the context of targeted immunization, parasitic infestation, and inflammation of mucosal tissues; plasma cell differentiation is impaired in B cells lacking Atg5 49 Cybb Cross an X‐linked Cybb null allele onto MRL.Faslpr mice Exacerbated lupus presentation, encompassing heightened splenomegaly, increased renal pathology, and altered profiles of elevated autoantibodies 110 Ncf1 Mice with Ncf1 m1j/m1j variant on a BALB/c.Q background Impaired NOX2 complex function; accumulation of secondary necrotic cells in phagocytes of mice, resulting in escalated production of inflammatory mediators 111 Atg7 Conditional deletion of Atg7 in hematopoietic cells (and their progenitors) Failure of differentiation into plasma cells and moderately decreased viability in Atg7‐deficient B cells 113 Rubcn Rubcn knockout in MRL.Faslpr lupus mice Heightened survival rates, attenuated nephritis, and lowered production of autoantibodies 115 Rubcn knockout in B6.Sle1.Yaa lupus mice Heightened survival rates, reduced nephritis, and decreased autoantibody production 115 Atg5 Conditional deletion of Atg5 in B cell Impaired antibody response; reduced numbers of antigen‐specific long‐lived plasma cells in the bone marrow; expanded endoplasmic reticulum (ER) size, intensified ER stress signaling and increased death in plasma cells 116 Conditional deletion of Atg5 in pro‐B cell Decreased spleen B cells, peritoneal B‐1a and B‐2 B‐cell proportions 117 Conditional deletion of Atg5 in mature B cell Decreased spleen B cells and peritoneal B‐2 B cells 117 Conditional deletion of Atg5 in mature B cell in C57BL/6lpr/lpr autoimmune‐prone mice Reduced production of antinuclear antibodies, decreased population of long‐lived plasma cells, and diminished accumulation of IgG in renal tissues 117 Atg7 Conditional deletion of Atg7 in B cell Impaired maintenance of memory B cells after immunization 118 Atg5 Conditional deletion of Atg5 in B cell in Tlr7.1 transgenic mice ANA and chronic inflammation did not develop; ameliorated glomerulonephritis; improved overall survival 125 Conditional deletion of Atg5 in dendritic cells in Tlr7.1 transgenic mice Increased lifespan and reduced IFNα level 126 Combined DC and B cell conditional deletion of Atg5 in Tlr7.1 transgenic mice Inflammasome activation and organ damage; splenomegaly and lymphadenopathy; severe lethality 126 MS Cybb Conditional deletion of Cybb in conventional dendritic cells Reduced the severity of EAE 28 Atg7 Conditional deletion of Atg7 in microglia Progressive MS‐like disease 141 Myeloid‐specific deletion of Atg7 Reduce severity of EAE 144 Pik3c3 Myeloid‐specific deletion of Pik3c3 Reduced severity of EAE 145 Atg5 Conditional deletion of Atg5 in CD11c dendritic cell Resistance of EAE induction 146 Atg7 Conditional deletion of Atg7 in dendritic cell Reduce the onset and severity of EAE 147 Pik3c3 Conditional deletion of Pik3c3 in dendritic cell Decreased occurrence and intensity of EAE 148 Rb1cc1 Conditional deletion of Rb1cc1 in dendritic cell Resistant to EAE induction 148 Rubcn Conditional deletion of Rubcn in dendritic cell Exhibit symptoms of EAE comparable to wild‐type control mice 148 Knockout Rubcn Exhibit symptoms of EAE comparable to wild‐type control mice 150 Pik3c3 Conditional deletion of Pik3c3 in CD4 cell Resistance of EAE induction 150 Becn1 Conditional deletion of Becn1 in CD4 cell Resistance of EAE induction 151 Atg5 Conditional deletion of Atg5 in microglia Exert no influence on the progression of EAE 152 IBD, inflammatory bowel diseases; SLE, systemic lupus erythematosus; MS, multiple sclerosis; IECs, intestinal epithelial cells; DSS, dextran sodium sulfate; LPS, lipopolysaccharide; ANA, antinuclear antibodies; ER, endoplasmic reticulum; NOX2 complex, NADPH oxidase 2 complex; EAE, experimental autoimmune encephalomyelitis; WT, wild type. John Wiley & Sons, Ltd. FIGURE 4 The roles of autophagy dysregulation in the pathogenesis of multiple sclerosis (MS). †Autophagy can act as a two‐edged sword in MS. While inhibiting autophagy may alleviate the inflammatory immune response by interfering with antigen presentation and specific T cell activation, it can also accelerate the accumulation of undesired substrates, such as apoptotic cells, myelin and axonal fragments, and protein aggregates. 4.3.1 Intracellular degradative pathway In microglia, the primary CNS‐resident macrophages, the machinery of autophagy performs an essential function in regulating phagocytosis, the process of engulfing and digesting unwanted substances, including cellular debris and protein aggregates, to promote tissue repair and homeostasis. 139 , 140 Autophagy receptors have been shown to recognize cargos and facilitate subsequent autophagic degradation. LAP, which is the functional convergence of autophagy and phagocytosis, is essential for clearing myelin debris. The gene Atg7, which is necessary for both canonical autophagy and LAP, is specifically deleted in the microglia of mice. This deletion leads to the development of a progressive MS‐like disease characterized by impaired autophagy‐associated phagocytosis. 141 Furthermore, studies conducted on mice with targeted deletion of Atg5 in microglia have demonstrated that the absence of Atg5 in these cells results in increased intracellular accumulation of myelin and inflammatory debris. This accumulation subsequently contributes to persistent neuroinflammation and neurotoxicity. 142 , 143 However, mice with microglial Ulk1 specifically deleted, a gene required only for canonical autophagy, did not exhibit a similar disease phenotype, suggesting that the disease phenotype was mainly dependent on noncanonical autophagy rather than canonical autophagy. 4.3.2 Antigen processing and presentation Experimental autoimmune encephalomyelitis (EAE) is an extensively used animal model to investigate MS, and many investigations have shown that modulation of autophagy leads to a significant improvement in the severity of EAE. Autophagy participates in the regulation of antigen loading onto MHC molecules and the subsequent antigen presentation by APCs, including dendritic cells and macrophages. Selective deletion of Atg7 or Pik3c3 specifically in myeloid cells of mice leads to a decrease in EAE severity, 144 , 145 indicating the therapeutic prospects of autophagy for EAE treatment. Additionally, selective deficiency of Pik3c3, Rb1cc1/Fip200, Atg5, or Atg7 in dendritic cells leads to a reduced occurrence and gravity of EAE, 146 , 147 , 148 , 149 primarily attributed to diminished handling and display of self‐antigens by APCs to CD4 T lymphocytes. Of note, mice lacking Rubcn, a gene essential for LAP but not canonical autophagy, in dendritic cells, displayed wild‐type levels of EAE susceptibility, which differs significantly from DC‐specific Pik3c3‐deficient or Rb1cc1‐deficient mice. 148 These findings suggest that the autophagy defect of these cells, rather than LAP, is responsible for EAE resistance, establishing a connection between autophagy and the processing of antigens as well as the pathogenicity of autoimmune T cells. 4.3.3 Activation and survival of T cells The hallmark of MS lies in the activation and proliferation of autoreactive CD4 T cells. 138 Research findings suggest that inhibiting autophagy can reduce the severity of EAE in animal models by regulating the activation and survival of autoreactive T cells. Specifically, mice with a T cell‐specific deletion of Pik3c3 or Becn1 displayed resistance to EAE induction and exhibited impaired ability to induce autoreactive T cell responses. 150 , 151 One underlying cause for this observation is the disrupted energy metabolism and functional dynamics of T cells, wherein autophagy is indispensable for supporting ATP production during the activation of T cells. As an exemplification, T cells lacking Pik3c3 exhibited suppressed oxidative respiration and diminished glycolysis, 150 leading to a failure in T helper 1 cell differentiation. Additionally, the maintenance of cell viability in activated T cells relies on autophagy, which facilitates the degradation of apoptotic proteins like Bim and Bcl‐2, effectively suppressing cellular apoptosis. Indeed, Becn1‐deficient T cells experience a significant increase in cell death upon stimulation. 151 Therefore, the modulation of autophagy in T cells presents a promising therapeutic strategy for MS. 5 THE THERAPEUTIC POTENTIAL OF TARGETING AUTOPHAGY Autophagy‐targeted drugs and biological agents have shown great potential as effective therapeutic options in autoimmune and inflammatory diseases. Several drugs have been used in clinical treatment, including rapamycin and hydroxychloroquine (HCQ). Clinical trials investigating various autophagy modulators are summarized in Table 3. Rapamycin and its analog, which are mTORC1 pathway inhibitors, can induce autophagy and have shown potential clinical efficacy in SLE based on several clinical trials. 153 , 154 , 155 , 156 A phase 1/2 open‐label prospective clinical trial provided compelling evidence that rapamycin exhibits safety, excellent tolerability, and significant clinical effectiveness in patients with SLE. 153 After 12 months of sirolimus therapy, a steady amelioration in disease activity manifested among patients diagnosed with active SLE. Moreover, there is supportive data for the efficacy of using rituximab to improve renal outcomes in patients with LN. 155 , 156 This includes notable reductions in proteinuria levels. Vitamin D, another autophagy inducer, have also been associated with the regulation of autoimmune diseases. 157 , 158 , 159 , 160 Autophagy inhibitors like chloroquine/HCQ, which raise the pH level within lysosomes and hinder the fusion between autophagosomes and lysosomes, 161 have been proposed as promising therapeutic choices with immunomodulatory effects for rheumatoid arthritis. 162 In addition to pharmacological modulators, peptide‐based agents are a novel therapeutic option. The evaluation of a Phase III trial is underway for a novel phosphopeptide, known as Lupuzor (P140), which exhibits autophagy‐inhibiting properties. A previous phase IIb clinical trial confirmed its safety and tolerability, 163 and Lupuzor demonstrated remarkable efficacy in reducing disease activity among individuals with a SLEDAI score of 6 or higher, presenting encouraging outcomes in advancing the treatment of lupus. TABLE 3 Several autophagy‐targeted drugs and biological agents and relevant clinical trials in inflammatory bowel diseases (IBD), systemic lupus erythematosus (SLE), and multiple sclerosis (MS). Agent Disease Trial ID Status Study title Intervention/treatment References Sirolimus (or rapamycin)—autophagy inducer IBD NCT00392951 Completed (Has Results) Sirolimus for Autoimmune Disease of Blood Cells Drug: sirolimus NA NCT02675153 Recruiting To Evaluate the Efficacy and Safety of Rapamycin for Crohn's Disease‐related Stricture Drug: rapamycin NA NCT04691232 Recruiting Autologous Ex Vivo Expanded Regulatory T Cells in Ulcerative Colitis Biological: autologous, ex vivo expanded, regulatory T cells NA SLE NCT00779194 Completed Prospective Study of Rapamycin for the Treatment of SLE Drug: rapamycin 153 NCT04582136 Not yet recruiting Efficacy and Safety of Sirolimus in Active Systemic Lupus Erythematosus Drug: sirolimus Drug: placebo NA NCT04736953 Not yet recruiting Sirolimus Treatment Of Patients With SLE Drug: sirolimus Other: placebo NA MS NCT00095329 Terminated Treating Multiple Sclerosis With Sirolimus, an Immune System Suppressor Biological: sirolimus NA Metformin—autophagy inducer IBD NCT05553704 Not yet recruiting Metformin in Patients With Ulcerative Colitis Treated With Mesalamine Drug: metformin NA NCT04750135 Not yet recruiting Assessment of Metformin as Adjuvant Therapy in Patients With Ulcerative Colitis Drug: metformin 500 mg TID oral tablet Drug: placebo NA SLE NCT02741960 Completed The Effect of Metformin on Reducing Lupus Flares Drug: metformin Drug: placebo 168 MS NCT05349474 Recruiting Metformin Treatment in Progressive Multiple Sclerosis Drug: metformin 500 mg oral tablet, up to four tablets a day Drug: placebo oral tablet identical to metformin, up to four tablets a day NA NCT04121468 Recruiting A Phase I Double Blind Study of Metformin Acting on Endogenous Neural Progenitor Cells in Children With Multiple Sclerosis Drug: metformin Other: placebo NA NCT05131828 Recruiting CCMR Two: A Phase IIa, Randomised, Double‐blind, Placebo‐controlled Trial of the Ability of the Combination of Metformin and Clemastine to Promote Remyelination in People With Relapsing‐remitting Multiple Sclerosis Already on Disease‐modifying Therapy Drug: metformin and clemastine in combination Drug: placebo NA NCT05298670 Recruiting Drug Repurposing Using Metformin for Improving the Therapeutic Outcome in Multiple Sclerosis Patients Drug: metformin 1000 mg oral tablet Drug: interferon beta‐1a NA Vitamin D—autophagy inducer IBD NCT00742781 Completed (Has Results) Vitamin D Supplementation in Crohn's Patients Dietary supplement: vitamin D NA NCT00621257 Terminated (Has Results) Vitamin D Levels in Children With IBD Dietary supplement: ergocalciferol Dietary supplement: cholecalciferol 158 , 169 NCT02208310 Terminated (Has Results) Trial of High Dose Vitamin D in Patient's With Crohn's Disease Drug: cholecalciferol 10,000 IU Drug: cholecalciferol 400 IU 170 NCT02076750 Completed Weekly Vitamin D in Pediatric IBD Dietary supplement: vitamin D3 (cholecalciferol) NA NCT01877577 Completed Supplementation of Vitamin D3 in Patients With Inflammatory Bowel Diseases and Hypovitaminosis D Dietary supplement: vitamin D3 NA NCT02615288 Completed High Dose Vitamin D3 in Crohn's Disease Dietary supplement: vitamin D3 171 NCT01692808 Completed Bioavailability of Vitamin D in Children and Adolescents With Crohn's Disease Drug: vitamin D3 3000 UI daily Drug: vitamin D3 4000 UI daily 172 NCT01369667 Completed Vitamin D Supplementation in Adult Crohn's Disease Dietary supplement: vitamin D3 Other: placebo 173 NCT02186275 Completed The Vitamin D in Pediatric Crohn's Disease Drug: vitamin D3: 3000 or 4000 UI/day then 2000 UI/day Drug: vitamin D3 800 UI/day then 800 UI/day NA NCT01187459 Completed Vitamin D in Pediatric Crohn's Disease Dietary supplement: vitamin D 174 NCT01864616 Terminated The Impact of Vitamin D on Disease Activity in Crohn's Disease Dietary supplement: vitamin D3 NA NCT03615378 Terminated Maintenance Dosing of Vitamin D in Crohn's Disease Dietary supplement: 5000 IU D3 Dietary supplement: 1000 IU D3 Dietary supplement: placebo NA NCT01046773 Terminated Vitamin D Supplementation as Nontoxic Immunomodulation in Children With Crohn's Disease Drug: cholecalciferol NA NCT04331639 Recruiting High Dose Interval Vitamin D Supplementation in Patients With Inflammatory Bowel Disease Receiving Biologic Therapy Dietary supplement: vitamin D3 NA NCT04828031 Recruiting Vitamin D Regulation of Gut Specific B Cells and Antibodies Targeting Gut Bacteria in Inflammatory Bowel Disease Drug: vitamin D NA NCT03999580 Recruiting The Vitamin D in Pediatric Crohn's Disease (ViDiPeC‐2) Drug: vitamin D3 NA NCT04225819 Recruiting Adjunctive Treatment With Vitamin D3 in Patients With Active IBD Dietary supplement: vitamin D3 Other: placebo NA NCT04991324 Not yet recruiting Cholecalciferol Comedication in IBD—The 5C‐study Drug: vitamin D3 NA NCT04308850 Not yet recruiting Exploring the Effects of Vitamin D Supplementation on the Chronic Course of Patients With Crohn's Disease With Vitamin D Deficiency Drug: vitamin D drops NA SLE NCT00710021 Completed (Has Results) Vitamin D3 in Systemic Lupus Erythematosus Drug: vitamin D3 Drug: vitamin D3 placebo 175 NCT01911169 Completed (Has Results) Vitamin D to Improve Endothelial Function in SLE Drug: cholecalciferol NA NCT01709474 Terminated (Has Results) Vitamin D3 Treatment in Pediatric Systemic Lupus Erythematosus Drug: vitamin D3 6000 IU Drug: vitamin D3 400 IU NA NCT05430087 Completed Vitamin D and Curcumin Piperine Attenuates Disease Activity and Cytokine Levels in Systemic Lupus Erythematosus Patients Drug: cholecalciferol (vitamin d3) and curcumin‐piperine. NA NCT01892748 Completed Cholecalciferol Supplementation on Disease Activity, Fatigue and Bone Mass on Juvenile Systemic Lupus Erythematosus. Drug: cholecalciferol Drug: placebo 160 , 176 NCT00418587 Completed Vitamin D Therapy in Patients With Systemic Lupus Erythematosus (SLE) Drug: cholecalciferol NA NCT01425775 Completed The Effect of Vitamin D Supplementation on Disease Activity Markers in Systemic Lupus Erythematosus (SLE) Drug: vitamin D 25(OH)D Other: placebo NA NCT05326841 Completed Effect of Cholecalciferol Supplementation on Disease Activity and Quality of Life of Systemic Lupus Erythematosus Patients Drug: vitamin D3 NA NCT03155477 Completed Effect Of Curcuma Xanthorrhiza and Vitamin D3 Supplementation in SLE Patients With Hypovitamin D Dietary supplement: “cholecalciferol” and “C. Xanthorrhiza” Dietary supplement: “cholecalciferol” and “placebo” 177 NCT05260255 Recruiting Effect of Vitamin D Supplement on Disease Activity in SLE Drug: vitamin D2 (calciferol) Drug: placebo NA NCT05392790 Recruiting Progressive Resisted Exercise Plus Aerobic Exercise on Osteoporotic Systemic Lupus Erythmatosus Other: progressive resisted exercise training Drug: calcium and Vit D Other: aerobic exercises NA MS NCT00940719 Completed Vitamin D3 Supplementation and the T Cell Compartment in Multiple Sclerosis (MS) Dietary supplement: vitamin D3 159 NCT01667796 Completed (Has Results) Pharmacokinetics of Vitamin D in Multiple Sclerosis and in Health Dietary supplement: vitamin D3 178 NCT01490502 Completed (Has Results) Vitamin D Supplementation in Multiple Sclerosis Drug: vitamin D3 179 NCT00644904 Completed Safety Trial of High Dose Oral Vitamin D3 With Calcium in Multiple Sclerosis Dietary supplement: vitamin D3 180 NCT01257958 Completed Vitamin D Pilot Study in Patients With Multiple Sclerosis Drug: vitamin D NA NCT01024777 Completed Safety and Immunologic Effect of Low Dose Versus High Dose Vitamin D3 in Multiple Sclerosis Drug: cholecalciferol NA NCT03385356 Completed Impact of Vitamin D Supplementation in Patients With Multiple Sclerosis Drug: vitamin D NA NCT02696590 Completed High Dose Oral Versus Intramuscular Vitamin D3 Supplementation In Multiple Sclerosis Patients Dietary supplement: vitamin D3 NA NCT00785473 Completed Can Vitamin D Supplementation Prevent Bone Loss in Persons With Multiple Sclerosis Dietary supplement: cholecalciferol Dietary supplement: calcium carbonate 181 NCT01440062 Terminated Efficacy of Vitamin D Supplementation in Multiple Sclerosis (EVIDIMS) Drug: verum arm receiving vitamin D oil Drug: low dose arm receiving neutral oil and 400 IU/g of vitamin D every second day 182 NCT03610139 Recruiting Longitudinal Effect of Vitamin D3 Replacement on Cognitive Performance and MRI Markers in Multiple Sclerosis Patients Dietary supplement: vitamin D3 NA NCT05340985 Not yet recruiting Investigating the Effects of Hydroxyvitamin D3 on Multiple Sclerosis Dietary supplement: 25(OH)D3 Dietary supplement: vitamin D3 NA Lupuzor/P140 peptide—autophagy inhibitor SLE NCT02504645 Completed (Has Results) A 52‐Week, Randomized, Double‐Blind, Parallel‐Group, Placebo‐Controlled Study to Evaluate the Efficacy and Safety of a 200‐mcg Dose of IPP‐201101 Plus Standard of Care in Patients With Systemic Lupus Erythematosus Drug: lupuzor Drug: placebo Other: standard of care NA EudraCT number:2007‐004892‐21 Completed Lupuzor/P140 Peptide in Patients with Systemic Lupus Erythematosus: A Randomised, Double‐Blind, Placebo‐Controlled Phase IIb Clinical Trial Drug: lupuzor Drug: placebo 163 No. 143/14.06.2006 (Bulgaria) Completed Spliceosomal Peptide P140 for Immunotherapy of Systemic Lupus Erythematosus Drug: lupuzor Other: standard of care 183 NCT01135459 Completed A Study to Evaluate the Efficacy and Safety of CEP‐33457 in Patients With Systemic Lupus Erythematosus Drug: lupuzor Drug: placebo NA NCT01240694 Terminated A Long‐Term Study of the Safety and Tolerability of Repeated Administration of CEP‐33457 in Patients With Systemic Lupus Erythematosus Drug: lupuzor NA Chloroquine/hydroxychloroquine (HCQ)—autophagy inhibitor IBD NCT01783106 Completed Antibiotics and Hydroxychloroquine in Crohn's Drug: ciprofloxacin Drug: doxycycline Drug: hydroxychloroquine Drug: budesonide 184 NCT05119140 Recruiting HCQ for Non‐Europeans With Mild to Severe UC Drug: hydroxychloroquine Drug: mesalamine NA SLE NA Completed Hydroxychloroquine in Lupus Pregnancy No HCQ exposure during pregnancy; continuous use of HCQ during pregnancy; cessation of HCQ treatment either in the 3 months prior to or during the first trimester of pregnancy 185 NCT00413361 Completed The Reduction of Systemic Lupus Erythematosus Flares: Study PLUS Drug: versus hydroxychloroquine 186 NCT01551069 Completed Multicenter Study Assessing the Efficacy & Safety of Hydroxychloroquine Sulfate in Patients With Systemic Lupus Erythematosus or Cutaneous Lupus Erythematosus With Active Lupus Erythematosus Specific Skin Lesion Drug: hydroxychloroquine (Z0188) Drug: placebo 187 NCT03019926 Completed Lupus and Observance Biological: hydroxychloroquine dosage NA NCT02842814 Completed Prediction of Relapse Risk in Stable Systemic Lupus Erythematosus Other: drug free Drug: HCQ Drug: GC+HCQ NA NCT01946880 Terminated (Has Results) Randomized MMF Withdrawal in Systemic Lupus Erythematosus (SLE) Drug: mycophenolate mofetil Drug: hydroxychloroquine or chloroquine Drug: prednisone NA NCT03802188 Recruiting Hydroxychloroquine in Systemic Lupus Erythematosus Observational study NA NCT03030118 Active, not recruiting Study of Anti‐Malarials in Incomplete Lupus Erythematosus Drug: hydroxychloroquine Drug: placebo oral capsule NCT03802188 Recruiting Hydroxychloroquine in Systemic Lupus Erythematosus Observational study NA MS NCT02913157 Completed Hydroxychloroquine in Primary Progressive Multiple Sclerosis Drug: hydroxychloroquine 188 NCT05013463 Recruiting Hydroxychloroquine and Indapamide in SPMS Drug: hydroxychloroquine pill Drug: indapamide pill NA Data were collected from the clinical registration website (http://clinicaltrials.gov/); IBD, inflammatory bowel diseases; SLE, systemic lupus erythematosus; MS, multiple sclerosis; NA, not available. John Wiley & Sons, Ltd. Moreover, recent investigations have focused on the modulation of autophagy to enhance immune responses and facilitate antitumor effects. Clinical trials targeting autophagy, either alone or in combination, in cancer treatment have mostly relied on HCQ, and the outcomes of these trials have been summarized in some recent reviews. 51 , 54 , 164 , 165 Despite some patients showing partial response or prolonged stable disease, overall response and survival rates have not been improved, leading to the exploration of more specific and targeted therapies. Due to its capacity to regulate the immune response against tumors, targeting autophagy has emerged as a promising strategy in the realm of tumor immunotherapy. For example, in a pancreatic cancer model, the combination of chloroquine‐mediated autophagy inhibition and the administration of immune checkpoint blockade (ICB) therapy targeting PD‐1 and CTLA‐4 has synergistically boosted the antitumor immune response. 56 By efficiently inhibiting tumor‐specific autophagy, there is a notable increase in antigen presentation, resulting in heightened responsiveness of PDAC to dual ICB. Furthermore, the implementation of this strategy enhances the infiltration of CD8+ T cells and facilitates the eradication of tumor cells. In addition to autophagy inhibitors, the induction of autophagy also holds promise for enhancing the efficacy of tumor immunotherapy. Studies have revealed the remarkable potential of a pH‐sensitive nanocarrier, which effectively regulates autophagy, in significantly augmenting the immunotherapeutic response during the treatment of osteosarcoma. This nanocarrier, when combined with PD‐1/PD‐L1 blockade, exhibits promising outcomes in enhancing the efficacy of immunotherapy. 166 Employing nanoparticles as a strategy to manipulate autophagy represents a promising approach for cancer treatment. These nanoparticles, serving as effective delivery systems, offer potential in leveraging autophagy for therapeutic applications. 167 While certain drugs mentioned above, including rapamycin and HCQ, have been approved for human use, their clinical application was not specifically targeted toward autophagy regulation. 24 Additionally, the extent to which the pharmacological effects rely on autophagy remains uncertain. Therefore, significant efforts are still required to advance the development of clinically viable interventions targeting autophagy. It is imperative to conduct in‐depth mechanistic investigations to elucidate the precise role of autophagy. Moreover, the development of autophagy modulators with specificity and the precise regulation of autophagic flux are crucial in order to maintain a delicate balance within autophagy processes, as excessive autophagy activity can also be harmful to cells. 6 CONCLUSIONS AND FUTURE DIRECTIONS This review emphasizes the essential role of autophagy in both innate and adaptive immune responses, encompassing crucial functions such as clearance of pathogens, processing and presentation of antigens, production of cytokines, and the survival and differentiation of lymphocytes. Malfunctioning of autophagy in humans can lead to various immune disorders, such as inflammatory, autoimmune or general immunity disorders. Inhibiting autophagy can alleviate diseases like SLE and MS by interfering with antigen presentation and lymphocyte survival, but it may also exacerbate diseases such as IBD. Dysfunctional autophagy can disrupt intestinal epithelial homeostasis, change gut microbiota composition, and amplify intestinal inflammation in IBD. These findings demonstrate that autophagy regulation varies across different diseases, tissues, and cells. Therefore, Therefore, future investigations should focus on elucidating the distinct roles of autophagy in different tissues and cell types, aiming to gain a comprehensive understanding of disease‐specific mechanisms. While many autophagy modulators are currently undergoing clinical trials, there are still several unresolved clinical questions. First, current pharmacological agents like rapamycin and HCQ indirectly modulate autophagy, and there is a lack of approved pharmaceuticals that specifically address autophagy as a therapeutic target. Second, the development of targeted therapies necessitates not only a drug with exceptional specificity but also a comprehensive understanding of the optimal timing and administration protocols. Methods for accurately quantifying the activity of the autophagy pathway in vivo are currently inadequate. Consequently, assessing the extent of autophagy modulation in patients undergoing therapy with autophagy modulators presents a significant challenge. Last, despite the promising therapeutic opportunities that autophagy has presented for effective cancer treatment, significant challenges and obstacles exist. Autophagy in tumor development exhibits a complex and multifaceted nature, encompassing both advantageous and detrimental contributions. Although the suppression of autophagy in certain scenarios can bolster the immune response and bolster the antitumor effects of immunotherapy, it can also contribute to immune evasion by tumor cells and foster resistance to treatment. Therefore, identifying the dominant role of autophagy (antitumorigenic or protumorigenic) in particular cancers and deciding when to target autophagy for treatment during tumor development are crucial questions. In conclusion, autophagy is integral to the maintenance of immune homeostasis and serves as a protective mechanism against inflammatory and autoimmune diseases. The suppression or enhancement of autophagy has been shown to have significant effects in various cell culture and animal models, impacting self‐immune responses, inflammatory conditions, and a variety of tumors. These discoveries have provided invaluable knowledge regarding the underlying mechanisms of these diseases and have paved the way for the emergence of groundbreaking therapeutic approaches. For instance, research has shown that effectively inhibiting autophagy effectively reduces the onset and severity of actively induced EAE, providing a compelling intervention strategy for autoimmune diseases informed by an animal model. 148 Furthermore, it may be crucial to identify suitable patients for personalized therapy by considering both disease pathology and genotype, such as individuals with IBD who possess the ATG16L1 T300A/T300A genotype. In addition to conventional treatment options, gene therapy emerges as a potential avenue for tackling IBD. Excitingly, several miRNAs have been discovered to effectively suppress autophagy. 189 Therefore, it is essential to develop more selective autophagy modulators, more reliable methods of quantifying autophagic activity in vivo, and more personalized therapeutic strategies. AUTHOR CONTRIBUTION Ting Gan conceptualized this review and drafted the manuscript. Shu Qu drew the figures and edited the language. Xu‐jie Zhou and Hong Zhang provided helpful suggestions on the structure and content of this review. All authors revised the manuscript. All authors have read and approved the article. CONFLICT OF INTEREST STATEMENT All authors have approved of the manuscript and declare no potential conflict of interest. ETHICS STATEMENT Not applicable. ACKNOWLEDGMENTS Figures were created with biorender.com. DATA AVAILABILITY STATEMENT All the presented information in this article is accessible by contacting the corresponding author. ==== Refs REFERENCES 1 Chiang WC , Wei Y , Kuo YC , et al. High‐throughput screens to identify autophagy inducers that function by disrupting Beclin 1/Bcl‐2 binding. ACS Chem Biol. 2018;13 (8 ):2247‐2260.29878747 2 Hampe J , Franke A , Rosenstiel P , et al. A genome‐wide association scan of nonsynonymous SNPs identifies a susceptibility variant for Crohn disease in ATG16L1. Nat Genet. 2007;39 (2 ):207‐11.17200669 3 Liu Z , Lenardo MJ . 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