Autophagy is categorised into three types based on the pathways through which substrates enter lysosomes: macroautophagy, microautophagy and chaperone-mediated autophagy (Figure 1) (Mahapatra et al., 2021). Among these, macroautophagy is the most extensively studied and crucial for anti-TB.

During nutrient deficiency, macroautophagy degrades proteins, fats, and glycogen to provide energy and metabolic substrates for cells (Lim and Murthy, 2020), preventing cell necrosis due to nutrient insufficiency. In nutrient abundance, macroautophagy clears misfolded proteins and damaged organelles, preventing their accumulation and subsequent damage, thus maintaining intracellular environmental stability. Therefore, macroautophagy balances energy sources under energy stress. The formation of autophagosomes is a dynamic process, initially forming a double-membrane structure known as a phagophore or separation membrane (Lu et al., 2022). The phagophore expands to enclose materials for degradation and eventually closes to form a complete double-membrane vesicle, the autophagosome (Zhao et al., 2022). The autophagosomal membrane may originate from intracellular membrane structures such as the endoplasmic reticulum, plasma membrane, Golgi apparatus, and mitochondria (He and Tian, 2020). Subsequently, the autophagosome traverses the cytoplasm to the lysosome and fuses with it to form an autolysosome (Sobolewski and Legrand, 2021). The lysosome contains various hydrolytic enzymes, such as proteases and lipases, which break down vesicle contents into basic metabolic products. These basic metabolic products are then released into the cytoplasm for reuse. The process of macroautophagy involves the regulation of various autophagy-related genes and signaling molecules, with its precise control being closely related to cell survival and metabolic balance and also playing a significant role in cancer, infection defense, and neurodegenerative diseases (Zhang C. et al., 2020; Zhu et al., 2022).

Compared to macroautophagy, which forms autophagosomes to enclose materials, microautophagy operates more directly. It involves morphological changes such as invagination or protrusion of the lysosomal membrane, encapsulating target materials, forming vesicles within the lysosome, and incorporating them into the lysosomal lumen for degradation, ultimately producing small molecules that are released back into the cytoplasm for cellular utilization (Yao and Shen, 2023; Li et al., 2024). This process does not require the formation of independent autophagosomes but relies on the dynamic reshaping of the lysosomal membrane to directly complete material uptake (Liu P. et al., 2023). Although less researched, microautophagy remains significant in maintaining intracellular environmental homeostasis, regulating energy metabolism, and responding to stress reactions.

Chaperone-mediated autophagy is a highly selective form of autophagy that utilizes molecular chaperones to recognize specific target proteins through distinct domains and transport them to lysosomes for degradation (Dubois et al., 2020; Liu et al., 2022). Its characteristics include strong substrate specificity, precise regulatory mechanisms, structural simplicity, and independence from membrane structure formation.

In this process, heat shock homolog 70kDa protein (HSC70) recognizes proteins containing the pentapeptide sequence Lys-Phe-Glu-Arg-Gln (KFERQ) and delivers them to lysosomes for degradation (Xu and Yang, 2022). Chaperone-mediated autophagy specifically identifies cytosolic proteins containing the KFERQ-like sequence, composed of specific amino acid residues: a glutamine (Q), an amino acid lysine (K) or arginine (R), a hydrophobic amino acid phenylalanine (F), valine (V), leucine (L) or isoleucine (I), an acidic amino acid glutamate (E) or aspartate (D), and ending with a hydrophobic or basic amino acid residue. This ensures strict substrate selectivity. The exposed KFERQ sequence is precisely recognised by cytosolic HSC70, forming a stable complex between the substrate and HSC70 and marking the initiation of chaperone-mediated autophagy. This complex is then transported to the lysosomal membrane where it binds to lysosome-associated membrane protein 2A (LAMP2A) (Bai et al., 2022). LAMP2A recognises and transports the substrate-chaperone complex into the lysosome (Zarrabi et al., 2023). Under the aggregation interaction of multiple LAMP-2As, unfolded substrate proteins pass through the lysosomal membrane into the lysosomal cavity (Jia et al., 2024), where they are degraded into small molecules by proteases. After degradation, the LAMP-2A multimer disassembles into monomers for recycling (Ho et al., 2020).

Autophagy depends on a set of proteins encoded by autophagy-related genes, which were initially discovered in yeast. To date, over 40 ATG proteins have been identified (Abd El-Aziz et al., 2021; Gao et al., 2024). ATG proteins play crucial roles at various stages of autophagy, including induction, formation and extension of isolation membranes, maturation of autophagosomes, and fusion of autophagosomes with lysosomes. During the initiation stage, the ULK1–ATG13–FIP200–ATG101 complex acts as the primary ATG activation module, which marks the beginning of autophagosome formation (Li et al., 2020). Subsequently, a Beclin1 (ATG6)-centred ATG protein complex mediates phagophore nucleation (Wang et al., 2023), with ATG14 conferring specificity to the Beclin1 complex for canonical autophagy. The expansion of the autophagosome membrane relies on two ATG-dependent ubiquitin-like conjugation systems: the ATG12–ATG5–ATG16 complex and LC3/ATG8 lipidation (He, 2022). Within these systems, ATG7 acts as an E1-like activating enzyme, which is essential for both conjugation pathways (Li H. et al., 2022). ATG5, meanwhile, serves as a key scaffold protein that is required for the elongation and stabilisation of the autophagosomal membrane (Cui et al., 2025). Dysfunction of the aforementioned ATG proteins will directly result in impaired autophagy flux.

Beyond their fundamental roles in autophagy regulation, functional abnormalities of autophagy-related genes and key proteins are closely associated with a wide range of diseases (Figure 2) (Zhang et al., 2023). In neurodegenerative disorders, impaired autophagy leads to defective clearance of misfolded proteins, such as tau and α-synuclein (Tian et al., 2020). In addition, heterozygous loss of Beclin1 results in autophagy deficiency and promotes tumorigenesis (Bradley et al., 2022). Autophagic homeostasis is essential for maintaining cardiovascular function and multi-organ integrity, and its disruption contributes to the development and progression of diseases affecting the liver, kidney, and respiratory system. Beyond these systems, autophagy also plays important physiological roles in regulating reproductive function, skeletal muscle metabolism, and ocular health (Chen and Lin, 2022). Collectively, autophagy-related genes and their key proteins form a multilayered regulatory network that precisely governs the dynamic process of autophagy.

M. tb employs multiple strategies to infect host cells and disrupt their normal activities, thereby evading immune clearance and achieving prolonged survival within them (Chen et al., 2021). In-depth research into the dynamic interaction between M. tb and host cells is crucial for developing new anti-TB treatments and inhibiting M. tb survival within host cells. This makes the study of the interaction between M. tb and host cells highly significant.

The pathogenicity of M. tb largely depends on its ability to infect the host and evade the immune response of host macrophages, including inducing macrophages towards an immunosuppressive phenotype, promoting macrophage foam cell formation, and manipulating cell apoptosis and autophagy. Macrophages, as the first line of defense of the host immune system against M. tb invasion, possess multiple functions such as bactericidal activity, phagocytosis, antigen presentation, and immune regulation (Wang et al., 2020). (1) Pathogen recognition and phagocytosis: M. tb, based on cell wall components such as lipoarabinomannan (LAM), phosphatidylinositol mannoside (PIM), and other outer membrane molecules, binds to macrophage membrane surface receptors such as mannose receptor (MR), complement receptor CR3, etc., thereby mediating phagocytosis (Wang et al., 2022). Subsequently, the phagosome fuses with the lysosome to form a phagolysosome, killing the pathogen through an acidic environment and hydrolytic enzymes. (2) Intracellular bactericidal and clearance: Macrophages can produce ROS, reactive nitrogen species (RNS), and various lysosomal enzymes to collectively clear M. tb (Shi et al., 2023). (3) Pro-inflammatory response and cytokine release: Upon recognizing M. tb, macrophages release inflammatory factors such as IL-6, TNF-α, etc., to regulate the cell’s nonspecific immunity against M. tb. (4) Antigen processing and presentation: Macrophages present processed antigen fragments to CD4⁺ T cells via MHC-II molecules, thereby inducing an immune response (Xu et al., 2022). (5) Granuloma formation and maintenance: At the site of M. tb infection, differentiated epithelioid cells, multinucleate macrophages, dendritic cells, B cells, and T cells collectively form granulomas to limit pathogen dissemination (HaileMariam et al., 2021). (6) Inducing programmed cell death and affecting the disease course: M. tb infection of macrophages can induce multiple forms of cell death, including apoptosis, necroptosis, unregulated necrosis, and pyroptosis. M. tb modulates these pathways by inhibiting host-protective apoptosis while promoting necrotic and pro-inflammatory forms of cell death, thereby influencing the host disease course and facilitating bacterial infection and transmission.

M. tb possesses various immune evasion mechanisms that enable it to survive within the host long-term and cause chronic infections. (1) Preventing fusion of phagosomes with lysosomes: After M. tb enters macrophages, it can secrete effector proteins that prevent the fusion of phagosomes with lysosomes, thereby avoiding subsequent elimination or degradation (Quan et al., 2022). (2) Antioxidant and anti-nitrogen intermediates: M. tb reduces the production of RNS and ROS intermediates to resist oxidative damage. (3) Inhibiting macrophage apoptosis and autophagy: M. tb keeps infected macrophages from undergoing apoptosis, prolonging the survival time of the pathogen within the cells (Mo et al., 2024). At the same time, it can regulate the fusion of autophagosomes with phagosomes, weaken lysosomal function, and inhibit cellular autophagy. (4) Suppressing antigen presentation: M. tb inhibits the expression of MHC-II molecule-related transcription factors and their molecules, weakening antigen presentation functions (Korbonits et al., 2022). (5) Establishing latent infection within granulomas: The host forms granulomas to suppress bacteria, while M. tb can enter a dormant state within the oxygen-deprived and nutrient-deficient granulomas, enhancing resistance to the environment and the host. Additionally, M. tb can employ other immune evasion mechanisms to maintain long-term survival under the pressure of the host immune system and drug treatment.

M. tb employs multi-level strategies to hijack the host autophagy pathway, thereby sustaining its intracellular survival and long-term infection. M. tb reduces pathogen degradation and suppresses antigen presentation and inflammatory responses by obstructing autophagosome maturation and lysosomal fusion, inhibiting autophagy initiation signals, and modulating host signaling pathways (Sit et al., 2020; Liu et al., 2020, Liu D. et al., 2023). These mechanisms facilitate bacterial evasion of immune defenses while also weakening the host’s adaptive immune response.

The PE/PPE/PGRS protein family is unique to the M. tb genome and accounts for around 10% of its coding capacity (Sharma et al., 2021). It is also closely associated with immunomodulation and virulence. Recent studies have demonstrated that PE_PGRS47 and PE_PGRS20 can directly interact with the host small GTPase Rab1A (Strong et al., 2021). This blocks the initiation of autophagy (Guallar-Garrido and Soldati, 2024), reduces the recruitment of autophagy-related proteins and suppresses the autophagic process, thereby enhancing bacterial survival within macrophages. These specific PE_PGRS proteins act as effectors that directly target core regulatory components of host autophagy, such as Rab1A and ULK1. These effectors impair autophagy and indirectly reduce pro-inflammatory cytokine production and antigen presentation efficiency (De Maio et al., 2020). In addition, the PPE51 protein has been shown to indirectly inhibit autophagy by suppressing the TLR2–ERK1/2 signalling pathway (Veerapandian et al., 2024). PPE51 expression attenuates host responsiveness to autophagy-inducing stimuli and interferes with TLR 2 signalling, leading to reduced activation of downstream kinases and consequently weakening autophagy-mediated antibacterial responses (Strong et al., 2022). Other PE/PGRS proteins, such as PE_PGRS41, have been reported to indirectly suppress autophagy-related defence responses by inhibiting host immune functions, including the production of cytokines and the activation of cell death pathways (Bo et al., 2023). This promotes the survival of the bacterium within host cells.

In summary, M. tb uses a variety of immunomodulatory proteins, including PE/PGRS and PPE, to precisely control host autophagy. This regulation involves the direct targeting of core autophagy molecules and signalling complexes, as well as the interference of pattern recognition receptor signalling and downstream inflammatory responses.

During M. tb infection, host cells can selectively recognize and eliminate intracellular pathogens through xenophagy. The bacteria rely on the ESX-1 secretion system to mediate phagosomal damage, cytosolic release, and ubiquitination (Kim et al., 2019). Bacterial DNA is recognized via STING, which further recruits autophagy adaptor proteins such as NDP52 and p62, thereby activating xenophagy (Ren et al., 2022). In this process, Smurf1 and Parkin play critical roles: Smurf1, an E3 ubiquitin ligase, primarily mediates k48-linked ubiquitination, whereas Parkin mainly participates in k63-linked ubiquitination (Campos et al., 2022). Together, they coordinate the tagging of intracellular pathogens and promote selective autophagy. Multiple studies have shown that the ubiquitin ligase Smurf1 is not only essential for anti-M. tb immunity but also contributes to the regulation of pulmonary inflammation and the activation of autophagy pathways, making it an indispensable regulator of host defense against tuberculosis.

LC3-associated phagocytosis (LAP) is a non-canonical form of autophagy that originates from invaginations in the plasma membrane, forming single-membrane phagosomes that are modified by the lipid LC3 (Judith et al., 2023). M. tb can activate TLRs, which, upon recognising pathogens, activate downstream signalling pathways and recruit PI3KC3 (VPS34) complex to single-membrane phagosomes. This catalyses the generation of PI3P, which, together with Rubicon, stabilises the NOX2 complex and drives ROS production (Wong et al., 2018; Nah et al., 2021). Various ATG proteins are then recruited to the phagosomal membrane, catalysing the formation of LC3-II and its surface modification. Ultimately, the phagosome fuses with the lysosome to complete the clearance of the pathogen. The LAP pathway can effectively prevent M. tb from inhibiting lysosomal maturation.

In summary, xenophagy and LC3-associated phagocytosis (LAP) function as core defense mechanisms against M. tb, jointly maintaining host anti-infective homeostasis (Figure 4). Elucidating their regulatory mechanisms provides important theoretical support for developing new strategies for tuberculosis prevention and treatment.

Research indicates that antibiotics can induce autophagy and enhance the bactericidal effect. First-line anti-TB drugs such as isoniazid and pyrazinamide activate autophagy in infected macrophages, thereby improving their ability to kill M. tb. In mouse models, a combination of clofazimine and rapamycin has been shown to significantly reduce the load of drug-resistant TB bacteria and improve pulmonary pathology. This combination also induces the production of multifunctional central memory T cells, thereby enhancing the host’s immune response (Singh et al., 2023). Combining vitamin D3 and phenylbutyrate promotes LC3-II expression, enhances autophagosome formation and improves the bactericidal activity of macrophages (Rao Muvva et al., 2021). Furthermore, certain small molecule compounds have been shown to limit the survival of M. tb in macrophages by enhancing the autophagy pathway (Berton et al., 2022).

Combining antibiotics with autophagy regulation agents is still challenging. Some autophagy activators induce autophagy and enhance antibacterial activity at low concentrations, but cause cytotoxicity and cell death at high concentrations (Peláez Coyotl et al., 2020). Furthermore, some autophagy activators interact pharmacokinetically with first-line anti-TB drugs, thereby affecting therapeutic efficacy; for example, the metabolism of rapamycin is impacted by rifampicin. Individual differences may also affect the activation of autophagy and therapeutic outcomes; therefore, treatment strategies must be tailored to the patient. Combining antibiotics with autophagy modulators shows great promise for TB treatment, and future research should explore the mechanisms of autophagy in anti-TB treatment.

Host-directed therapy (HDT) is a novel adjunctive treatment approach that modulates host immune responses, promotes the production of antimicrobial peptides, autophagy, and other macrophage effector mechanisms, alters the inhibitory mechanisms of pulmonary inflammation and matrix destruction (Wallis and Hafner, 2015), enhances the host ‘s innate and acquired immunity, assists in clearing pathogens, reduces lung tissue damage caused by inflammatory responses, shortens treatment duration, and improves treatment outcomes. HDT provides new methods for the treatment of drug-resistant TB and hosts with weakened immune function. Numerous studies have shown that various known drugs have the potential for HDT, such as vitamin D, which kills intracellular M. tb through the production of antimicrobial peptides; rapamycin, which inhibits the growth of M. tb in macrophages and reduces the replication of M. tb in the lungs by activating autophagy; statin drugs have immunomodulatory and anti-inflammatory properties and can inhibit the mTOR signaling pathway, promoting cellular autophagy and phagosome maturation (Hassanpour et al., 2019), among which simvastatin exerts its anti-TB effect by regulating cholesterol metabolism. Although HDT is still in the preclinical stage, it provides a new treatment approach for TB, especially drug-resistant TB and immunocompromised populations, laying a theoretical foundation for individualized treatment plans that combine antibacterial and host regulation.

Although studies have shown that M. tb can evade host autophagy clearance through various mechanisms, such as interfering with autophagy signalling pathways and inhibiting the fusion of autophagosomes with lysosomes, the specific mechanisms remain unclear. Furthermore, the question of whether M. tb employs different autophagy evasion strategies during latent and active TB infection is a topic that has not been widely studied. Therefore, developing a comprehensive understanding of the dynamic interaction between M. tb and autophagy could offer new perspectives for clinical treatment.