Many investigations have identified TGF-β as the key molecule in many human fibrotic conditions, and TGF-β promotes the process of fibrogenesis in tissue cells and the extracellular matrix (21–23). It is currently well accepted that the TGF-β/small mother against decapentaplegic (Smad) pathway is a major signaling pathway leading to lung fibrosis resulting from many diseases (24). Among the TGF-β family members, TGF-β1 is considered the “master switch” for fibrosis (25, 26). The specific signaling pathway is as follows: TGF-β recognizes and binds transforming growth factor β receptor II (TGFβRII), which then phosphorylates transforming growth factor β receptor I (TGFβRI). After phosphorylation of TGFβRI, Smad2 and Smad3 are phosphorylated and form a heterotrimeric complex with Smad4 to translocate into the nucleus and regulate the expression of target genes and the transcription of profibrotic molecules, including α-smooth muscle actin (α-SMA), collagen I and tissue inhibitors of matrix metalloproteinases (TIMPs) (27). Then, these profibrotic molecules induce myofibroblast activation, matrix deposition, and epithelial-to-mesenchymal transition (EMT) to cause fibrosis. In addition, recent studies have identified the action of profibrotic microRNAs and long noncoding RNAs induced by the TGF-β/Smad signaling pathway in pulmonary fibrosis (28).

Roberts et al. found that Smad3 contributes to the pathogenic effects of TGF-β (29). This group observed that loss of Smad3 can block TGF-β-mediated epithelial-to-mesenchymal fibrosis and attenuate the development of fibrotic sequelae of ocular and renal injury in mice with targeted deletion of Smad3. Moreover, Cao and colleagues demonstrated that polydatin mitigates pulmonary fibrosis caused by irradiation by inhibiting the TGF-β/Smad signaling pathway and the EMT process (30). Park et al. identified that EW-7197, a novel small molecule inhibitor of TGF-β type I receptor kinase (ALK5), can inhibit pulmonary fibrosis by blocking the TGF-β/Smad signaling pathway and can decrease the expression of collagen, α-SMA, and fibronectin in mice (31). These studies confirm that the TGF-β/Smad signaling pathway is the crucial signaling pathway of RILI. Recently, new research has proven that RAS-responsive element binding protein 1 (RREB1) is a RAS-regulated Smad cofactor that drives the expression of profibrotic genes in EMT, which deepens our understanding of the association between the RAS and TGF-β pathways for the coordinated induction of EMT (32). Multiple approaches that interfere with the TGF-β/Smad signaling pathway have shown protective effects in preclinical models of pulmonary fibrosis (33). Therefore, further study of this pathway is expected to identify new therapeutic targets for pulmonary fibrosis. Indeed, many recent clinical trials have recently evaluated the anti-inflammatory and antifibrotic effects of TGF-β signaling pathway inhibition.

HMGB1, an HMG protein, senses and coordinates the cellular stress response and functions as a damage-associated molecular pattern. HMGB1 exerts widespread biological effects throughout the body, including effects on metabolism, inflammation, immunity and cell death (34–36). In addition, many studies have verified that HMGB1 participates in lung inflammation and lung injury (37–39). The underlying mechanisms by which HMGB1 induces lung inflammation include several activated signaling pathways: ERK, JNK, PI3K/Akt, JAK and NF-κB (34). Although HMGB1 has been demonstrated to be involved in lung inflammation, its role in RILI has not been explicitly revealed. Generally, nuclear HMGB1 acts as a DNA chaperone involved in physiological processes such as DNA replication and transcriptional regulation, and extracellular HMGB1 actively secreted by immune cells or passively released by nonviable and injured cells regulates cell proliferation and inflammation by binding to multiple surface receptors, such as Toll-like receptor 2 (TLR2), Toll-like receptor 4 (TLR4), and receptor for advanced glycation end products (RAGE) (40). Reports indicate that blocking the HMGB1 signaling pathway can protect against early RILI and attenuate radiation-induced vascular injury, identifying a potential signaling pathway in RILI (41–43). Macrophages killed by high-dose irradiation can secrete HMGB1 to activate NF-κB through binding to TLR4, leading to an inflammatory response, and this process has been proven by Mei and colleagues (44, 45). Recently, a series of investigations have identified the role of the HMGB1/TLR4 signaling pathway in lung injury. Meng and coworkers identified the protective effect of dexmedetomidine in lung injury through the HMGB1-mediated TLR4/NF-κB pathway (46), and Liu et al. reported that fibroblast growth factor 10 exerts anti-inflammatory and cytoprotective effects to alleviate particulate matter-induced lung injury by inhibiting the HMGB1/TLR4 pathway (47). These studies suggested that HMGB1 plays an important role in mediating RILI and that the HMGB1/TLR4 pathway is a crucial signaling pathway that mediates RILI. Research has confirmed that HMGB1/TLR4 pathway activity induces RILI through downstream effectors such as NF-κB, JNK, and ERK1/2 and that this process can be inhibited by glycyrrhizin (48). The identification of the HMGB1/TLR4 signaling pathway elucidates the pathogenesis of RILI from a new perspective and identifies potential therapeutic targets for RILI.

The nuclear factor erythroid 2 related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway is one of the most important mechanisms in the body’s defense against oxidative stress. Nrf2 is an original member of the mammalian cap ‘n’ collar transcription factor family with a highly conserved basic region-leucine zipper (bZIP) motif (49), and contributes to the anti-inflammatory process and anti-oxidative stress response by orchestrating the recruitment of inflammatory cells and regulating gene expression through ARE (50–52). Under physiological conditions, Nrf2 is sequestered by Kelch-like ECH-associated protein 1 (Keap1) in the cytosol. However, under oxidative stress, such as that induced by radiation, Keap1 is modified and leads to the release of Nrf2, which translocates to the nucleus and activates ARE to express ARE-dependent genes for the oxidative stress response. Nrf2 contains three nuclear localization signals (NLSs), namely, NLS1, NLS2, and NLS3, which are critical for the nuclear import of Nrf2 (53). The translated gene products exert cytoprotective effects against ROS and include, including heme oxygenase-1 (HO-1), glutathione S-transferase (GSTs), the aryl hydrocarbon receptor (AhR), uridine 5’-diphospho-glucoronyl transferase (UGT), and sulfotransferases (SULTs) (51). For instance, HO-1 can catalyze the freeing of heme-bound Fe to generate biliverdin, and biliverdin can then be reduced to bilirubin with the generation of carbon monoxide to exert an anti-inflammatory effect (54). With radiotherapy-induced accumulation of ROS in lung tissue, the Nrf2/ARE signaling pathway plays a critical role in the maintenance of cellular homeostasis under oxidative stress (55–57).

Mathew and colleagues found using wild-type and genetically engineered mif (-/-) mice exposed to 20 Gy single-fraction thoracic radiation that migratory inhibition factor (MIF) may contribute to age-related susceptibility to thoracic radiation via Nrf2 (58). Similarly, Traver and coworkers found that loss of Nrf2 promotes loss of alveolar type 2 cells, whose injury initiates a fibrotic response, in different C57BL/6 mice exposed to a thoracic radiation dose of 12 Gy (59). However, the results of their investigations are consistent with those of a previous study verifying that Nrf2 deficiency reduces the life span of mice administered thoracic irradiation (60). Duru et al. confirmed the radioprotective role of Nrf2 in RILI via direct binding to the miR-140 promoter and elucidated the mechanism by which irradiation promotes Nrf2 nuclear translocation and subsequent activation of ARE-dependent genes (61). Furthermore, another investigation showed that Nrf2 deficiency exacerbates but Nrf2 overexpression significantly alleviates radiation-induced histopathological damage (62). All of these studies supported the protective role of Nrf2 in RILI, but the downstream mechanisms are largely unexplored. Therefore, focusing on the Nrf2/ARE signaling pathway may aid in the prevention and treatment of RILI.

In addition to the abovementioned signaling pathways, other possible pathways, such as melatonin-mediated miR-30e/nucleotide-binding domain-like receptor protein 3 (NLRP3), chemokine C-C motif ligand 2 (Ccl2), and Wnt/β-catenin signaling pathways, may play an important role in mediating RILI (63–65). Recently, research has also showed that ferroptosis inhibitors tremendously alleviate RILI, indicating the role of ferroptosis in RILI (66, 67). Similar to radiation-induced toxicity in head and neck cancers, single nucleotide polymorphisms of DNA repair and apoptosis genes may influence the severity of radiation-induced toxicity in RILI since data have confirmed involvement of ERCC1, ERCC5, TP53 and MDM2 in radiation-induced toxicity in head and neck cancer (68). Those results showed that relevant single nucleotide polymorphisms in DNA repair (ERCC1 and ERCC5) and apoptosis (MDM2 and TP53) genes might be linked to a higher risk of several grade 3-4 adverse effects including dermatitis, cervical skin fibrosis, xerostomia, and osteoradionecrosis. A profound recognition of signaling pathways underlying RILI would contribute to its prevention and control and provide potential therapeutic targets and strategies. Thus, much exploration and discovery is still needed to completely determine the signaling pathways of RILI.

Additionally, dosimetric factors play a critical role in RILI. There are few doubts that dosimetric parameters including irradiated volume, mean lung dose (MLD), dose delivered, schedule, and tumor location are risk factors for RILI (69, 70). Among these parameters, MLD is a key risk factor, and several studies have elucidated various cutoffs that associate with RILI (e.g. 16-18 Gy) (70, 71). Other studies have revealed associations with V20 and V30 (lung volume receiving 20 or 30 Gy, respectively) (72, 73), and V20-V40 for the postoperative setting (74).

In efforts to reduce dose exposure to by the normal lung, several new technologies have been recently developed. For instance, the magnetic resonance imaging linear accelerator (MR-Linac) provides more detailed real-time visualization of the tumor and surrounding tissue anatomy and facilitates the more precise use of adaptive re-planning (75). Additionally, proton beam therapy takes advantage of the unique biological properties of heavy ions (e.g. the proton), which deposits maximal dose at a certain point (the Bragg peak), distal to which there is a very sharp dropoff in dose including virtually no dose as the beam exits the patient (76, 77).

Many signaling pathways are activated under radiation stress, such as the main pathways introduced above. A common effect of these pathways is collagen aggregation. In the clinic, glucocorticoid drugs are the mainstay of RILI treatment. As the understanding of the mechanism of RILI has deepened, many drugs that can precisely target molecules in these signaling pathways or affect their common components have been identified. TGF-β is increasingly recognized for its role in the tumor environment. TGF-β not only can promote inflammation and fibrosis of the lung under radiation but also has an essential effect on tumor progression and escape (78). Many clinical trials have focused on inhibition of the TGF-β pathway to increase the curative effect and reduce side effects. There are four main types of drugs that inhibit the TGF-β pathway: anti-TGF-β antibodies, such as AVID200 (NCT03834662), GS-1423 (NCT03954704), NIS793 (NCT02947165), and BCA101 (NCT04429542); anti-TGF-β receptor antibodies, such as galunisertib (NCT02452008) and bintrafusp alfa (NCT04481256); small molecule inhibitors of TGF-β receptor serine/threonine kinase, such as SH3051 (NCT04423380); and anti-latent TGF-β monoclonal antibodies, such as SRK-181 (NCT04291079). Pirfenidone, an anti-inflammatory drug, is approved for use in patients with idiopathic pulmonary fibrosis (79–82). Pirfenidone can inhibit the TGF-β pathway to decrease radiation-induced tissue fibrosis (83). Researchers found that TGF-β release from M2 alveolar macrophages is decreased with pirfenidone treatment (84). In addition, pirfenidone affects the Nrf2 signaling pathway. One article reported that Nrf2 expression was upregulated in mice with lung fibrosis treated with pirfenidone, which revealed that pirfenidone may have an anti-oxidative effect (85). Glycyrrhizin can inhibit the HMGB1/TLR4 signaling pathway, therefore potentially attenuating RILI (48). Nintedanib, a kinase inhibitor that blocks VEGFR/PDGFR/FGFR, is another drug approved for idiopathic pulmonary fibrosis, and it can also be used to treat advanced non-small cell adenocarcinoma (86). It can also inhibit collagen aggregation, thereby ameliorating lung fibrosis (87). Some researchers have also found that nintedanib can inhibit fibrosis by means of suppressing activation of the TGF-β pathway (88, 89). However, the specific mechanisms are unclear. Endostar is an angiogenesis inhibitor that can attenuate liver fibrosis (90), and also can suppress scar formation in hypertrophic conditions by reducing VEGF expression (91, 92). Some researchers have explored whether Endostar can attenuate lung fibrosis after radiation therapy in non-small cell lung cancer (NSCLC) patients in clinical trials, although the results have not yet been reported. Enalapril, an angiotensin converting enzyme inhibitor, also plays an important antifibrotic role (93). Some researchers found that enalapril can suppress NF-kB signaling pathway activation in the context of pulmonary hypertension (94). The NF-kB pathway can promote fibrosis, as mentioned above. Further studies showed that enalapril can attenuate lung fibrosis caused by radiation (95). Next, AEOL10150 is an antioxidant that can catalyze ROS dismutation and alleviate ROS-mediated injury in rhesus macaques (96, 97). Tocilizumab, an anti-IL-6 receptor antibody, can reduce the inflammatory cytokine storm in patients with severe disease and increase mortality to some degree (98, 99). However, whether the drug has any effect on RILI remains to be studied. Canakinumab is an IL-1β antibody that has a potential effect on NSCLC progression and inflammation caused by IL-1β (100). Naringenin has also been proven to reduce RILI by decreasing the production of IL-1β (101).

We have already mentioned TGF-β as a contributor to both RILI and IRLI, and the TGF-β/Smad signaling pathway as one of the most crucial pathways leading to pulmonary fibrosis. Moreover, TGF-β is not only the master regulator of fibrosis (27,149), but also plays a context-dependent role, and its biological effects are complex—it plays diverse roles in the regulation of cell proliferation and differentiation, wound healing, and the immune system, as well as key roles in pathologies, including fibrosis and cancer (150–152). The role of elevated plasma TGF-β during radiotherapy has long been recognized to predict a higher risk of developing pulmonary toxicity (153). After irradiation damage, TGF-β secreted by immune cells such as neutrophils, monocytes, and lymphocytes initiates a series of events leading to aseptic inflammation and pulmonary fibrosis; these events consist of increased expression of α-SMA, cell transformation into protomyofibroblasts and EMT. In addition, TGF-β plays a key regulatory role in immune responses and cancer progression (154–156), and it plays an undeniable role in cancer immunotherapy (78). Recently, Liu et al. confirmed that TGF-β suppresses Th2-cell-mediated cancer immunity, which promotes vessel remodeling, and that depletion of TGFBR2 in CD4+ T cells can suppress cancer progression via tissue healing and remodeling of the blood vasculature (157); thus, this group designed a strategy for targeted TGF-β signaling blockade in Th2 cells, which significantly inhibited tumor growth in mice (158). TGF-β signaling shows tremendous potential as an immunotherapy for the tumor microenvironment and has broad prospects in cancer treatment.

Here, we primarily discuss the TGF-β signaling pathway in immune checkpoint inhibitor-induced lung injury. With the use of immune checkpoint inhibitors, the T cell inhibitory signal is silenced, and activated T cells then stimulate generalized immune activation as well as the production of numerous cytokines, including TGF-β. In addition to the canonical TGF-β/Smad signaling pathway, TGF-β can also activate the MAPK, ERK, JNK, and PI3K pathways directly by ligand-bound receptors that modulate downstream cellular responses, including contributions to EMT, interactions with TGF-β/Smad signaling, or antagonism of Smad-mediated effects (159, 160). In addition, TGF-β is key to maintaining tolerance to self-antigens, and PD-L1 and TGF-β exhibit synergism in promoting Treg development (156). At sites of immune privilege or inflammation where TGF-β is present, PD-L1 may promote de novo generation of Tregs (161). Therefore, when we use PD-L1 blockade to treat cancer, the interaction between PD-L1 and TGF-β may be influenced, and the immune balance may be disrupted, damaging normal tissue. Therefore, the TGF-β signaling pathway may be one of the most important pathways in the crosstalk between RILI and IRLI.

The link between recognition of microbial nucleic acids and activation of innate immune responses has been explored for several decades and was finally revealed to be the cGAS-STING pathway (162–164). In addition to mediating a protective immune response to infection, the cGAS-STING pathway can also detect tumor-driven DNA and impart antitumor immunity as well as play a role in the development of various inflammatory conditions (165–167). Under physiological conditions, cytosolic DNA is not present; thus, cGAS remains in an autoinhibitory state. However, under pathophysiological conditions, accumulated cytosolic DNA resulting from many harmful factors can be recognized by cGAS, which forms an oligomeric (2:2) complex with this DNA (168). DNA binding induces switch-like conformational changes in the activation loop of cGAS, which catalyzes the synthesis of 2’3’-cyclic GMP-AMP (cGAMP) from ATP and GTP (168, 169). 2’3’-cGAMP and other cyclic dinucleotides of bacterial origin can bind to STING and mediate the activation of IRF-3 by TANK-binding kinase 1 (TBK1), which translocates to the nucleus and initiates the transcription of the IFN-β gene (169, 170). In addition, STING activates NF-κB and induces the expression of inflammatory cytokines such as TNF, IL-1β and IL-6 in cooperation with TNF receptor-associated factor 6 (TRAF6), NF-κB essential modulator (NEMO), IKKβ, and TBK1 (162, 171–173).

We previously noted that a primary initiator of RILI is direct DNA damage, which then triggers intracellular signaling. Furthermore, mitochondrial DNA damage resulting from irradiation and ROS also provokes a series of inflammatory and immune responses and is more sensitive to the absence of repair mechanisms than is nuclear DNA damage (4). Since damaged DNA is released from nuclei or mitochondria, it is sensed by cGAS-STING signaling and leads to myriad biological consequences (162, 174). Mitochondrial damage and mtDNA have been reported to result in activation of the cGAS-STING pathway, leading to renal inflammation and fibrosis, which is similar to pulmonary inflammation and fibrosis (175). When radiation-induced DNA damage occurs, the DNA damage response (DDR) is activated depending on the context of damage and this is mediated by the central DDR kinases. There is an inextricable link between DDR signaling directly upstream of type I IFN signaling and it is shown that micronuclei link DNA damage by radiotherapy and/or DDR inhibitors to cytoplasmic nucleic acid sensors and type I IFN signaling (176, 177). Loss of function or inhibitors against numerous key DDR kinases have been shown to induce type I interferon production (178). Thus, DDR inhibitors can not only inhibit DNA repair and increase the sensitivity of radiotherapy, but also increase the number of micronucleus and small fragments of DNA in tumor cells induced by radiotherapy, and further activate the cGAS-STING pathway and the expression of type 1 IFN. As mentioned before, Borchiellini et al. have confirmed that relevant single nucleotide polymorphisms in DNA repair (ERCC1 and ERCC5) genes might influence the severity of radiation-related side-effects in HNSCC patients and others have verified that the inhibition of checkpoint kinase 1 and 2 (which activate cell-cycle checkpoints and serve a critical role in the DDR reduced NOTCH signaling) enhances the in vitro and in vivo response of HNSCCs to radiation (68, 179). These results all support the potential role of DDR inhibitors in radiation-induced toxicity and combination with RT. Additionally, based on cancer-associated DDR defects, DDR inhibitors as tumor-selective radiosensitizers may allow improved tumor control without increased normal tissue toxicity which reduces the incidence of RILI. In addition, the role of cGAS-STING signaling in lung inflammation and lung fibrotic diseases has been elucidated (147). Moreover, the cGAS-STING signaling pathway is closely related to natural antitumor immunity as well as immune checkpoint inhibitor therapy, which implies the potential of targeting this pathway to mediate IRLI (180, 181). When immune checkpoint inhibitors silence inhibitory signals for T cell activation and activate an effective antitumor response, accumulation of self-DNA released from dying tumor cells triggers the cGAS-STING pathway to induce the production of interferons and inflammatory cytokines (182). Activation of the cGAS-STING pathway can not only mediate innate antitumor immunity and produce synergistic antitumor effects with immune checkpoint inhibitors but also can elicit a robust inflammatory response by activating NF-κB and stimulating the production of inflammatory cytokines such as TNF, IL-1β, and IL-6 (181, 183). However, few investigations on the cGAS-STING pathway in RILI and IRLI have been conducted; thus, more research is needed to explore the role of cGAS-STING in lung injury.

Pyroptosis is defined as a form of regulated cell death (RCD) that critically depends on the formation of plasma membrane pores by members of the gasdermin protein family, often (but not always) as a consequence of inflammatory caspase activation (184, 185). It occurs widely in all kinds of cells and leads to an inflammatory cascade response through the release of IL-1β and IL-18 (unlike the immune-silencing effect of apoptosis) (186, 187). Cheng et al. found that caspase-11-mediated endothelial pyroptosis underlies endotoxemia-induced lung injury (188), and several studies have addressed NLRP3 inflammasome- and AIM2 inflammasome-mediated pyroptosis in lung injury (189–192). Lung injury, especially pneumonitis, occurs more often as a result of the inflammatory response due to radiotherapy or immunotherapy. Therefore, pyroptosis may likely be the common downstream signaling pathway of RILI and IRLI.

A considerable number of studies have addressed the key role of pyroptosis in lung injury (189–191, 193, 194). Accumulating evidence suggests that NLRP3 inflammasome- and AIM2 inflammasome-mediated pyroptosis in both macrophages and epithelial cells plays a critical role in the development of radiation-induced tissue injury (195, 196). Generally, double-stranded DNA breaks caused by ionizing radiation can be recognized by the AIM2 inflammasome, which then activates the process of pyroptosis (197, 198). AIM2 translocates into the nucleus, localizes at the foci of double-stranded DNA breaks, and recruits ASC, which leads to caspase-1 activation. The active caspase-1 induces pore formation on the plasma membrane through the cleavage of gasdermin D. With the cleavage of gasdermin D, the enzymolysis and release of IL-1β and IL-18 lead to inflammation around the site. Otherwise, radiation-induced pyroptosis in bone marrow-derived macrophages mediated by the NLRP3 inflammasome is initiated by the recognizing of NLRs to PAMPs and DAMPs, and the downstream process is as described above (196, 199). Based on the evidence, a new study has showed that inhibition of AIM2 inflammasome-mediated pyroptosis by andrographolide contributes to amelioration of radiation-induced lung inflammation and fibrosis, further confirming the important role of pyroptosis in RILI (192). They found that andrographolide effectively prevented AIM2 from translocating into the nucleus to sense DNA damage induced by radiation in bone marrow-derived macrophages. Moreover, Wu and coworkers verified the effect of 5-androstenediol to prevent radiation injury in mice though inhibiting radiation-induced activation of caspase-1 and GSDMD by decreasing the interaction between AIM2 and ASC, which indicates that the AIM2 inflammasome is a key signaling pathway in radiation-induced lung injury (200). Han and colleagues preliminary confirmed that NLRP3 inflammasome induces pyroptosis in mice with radiation-induced lung injury though the detection of a series of pyroptosis related molecules (201).

Pyroptosis is also closely related to IRLI. As mentioned above, normal lung tissue cells are attacked and damaged due to generalized immune activation from checkpoint neutralization, preexisting autoantibodies, and off-target effects of T cell-mediated immunity. With lysis of these (along with neoplastic) cells, double-stranded DNA and endogenous danger signals may be recognized by the AIM2 inflammasome and DAMPs may be recognized by the NLRP3 inflammasome. This may mediate pyroptosis of tissue cells leading to pneumonitis in IRLI, similar to the events of pyroptosis in RILI. IL-1β and IL-18, as the products of inflammasome activation, result in proinflammatory T cell differentiation and target organ damage (186, 202). Moreover, PD-L1 in the nucleus may be closely associated with pyroptosis in tumor cells. A recent study proved that under hypoxic conditions, PD-L1-mediated gasdermin C expression can switch apoptosis to pyroptosis in cancer cells (203). This research shows a non-immune checkpoint function of PD-L1 and indicates that pyroptosis is likely the key signaling pathway in immunotherapy, inflammation, and tumor necrosis. Moreover, diversification of cell death has been valued for the interaction between antitumor immunity and distinct cell death mechanisms (204, 205). Wang et al. revealed the antitumor immune function of pyroptosis through a bioorthogonal system, finding that pyroptosis-induced inflammation contributes to robust antitumor immunity and can synergize with immune checkpoint blockade (206). Another study showed that gasdermin E can suppress tumor growth by granzyme B in killer cells, triggering caspase-independent pyroptosis in cancer cells (207). Similarly, Zhou et al. found that granzyme A released from cytotoxic lymphocytes cleaves gasdermin B to trigger pyroptosis in target cells and that PD-1/PD-L1 blockade can activate T cells to promote gasdermin B-mediated pyroptosis to kill cancer cells (208). However, in this process, the inflammatory response may be enhanced with the release of IL-1β and IL-18, and pyroptosis of cancer cells may lead to possible injury to normal cells in the tissue. On the other hand, Yang and coworkers attempted to summarize the role of inflammasomes on innate immunity and the natural history of autoimmune diseases. They showed that inflammasomes play a key role in lowering the threshold of immunity, thereby potentiating a number of autoimmune diseases (209). Si Ming Man et al. elaborated on the role of AIM2 inflammasomes in cancer and autoimmunity, that inappropriate recognition of cytoplasmic self-DNA by AIM2 contributes to the development of psoriasis, dermatitis, arthritis, and other autoimmune and/or inflammatory diseases (210). These investigations indicate the potential relationship between pyroptosis and autoimmunity, which is similar to the postulated mechanisms of IRLI. Nevertheless, there remains a lack of robust evidence to support the mechanism of pyroptosis in IRLI, and this area needs to be further explored.