T cells play a key role in regulating tumor growth and metastasis. Among them, CD4+ T cells can be differentiated into Th1, Th2 and regulatory T cells (Tregs) according to different functions and markers. Th1 regulates immune cell function by increasing the activity of silence-message regulatory factor-associated enzyme 1 (SIRT1) dependent on nicotinamide adenine dinucleotide (NAD), thereby exerting anti-tumor effects (39). Th2 is generally believed to play an anti-tumor role through the expression of eosinophilic and eosinophilic chemotactic factor (ECF), and some scholars have also proved that TH2 can play a pro-tumor role through the secretion of cytokines IL-4 and IL-5 (40). More researchers profess the importance of Th1/Th2 imbalance leading to impaired immune function and augmented escape of tumor cells, thus promoting tumor formation (41). At the same time, studies have shown that Th1/Th2 imbalance in peripheral blood is closely related to TB nosogenesis (42). TB patients show reduced Th1 response and/or enhanced Th2 response (43), and the severity of the disease is closely related to Th1 response, the lower the Th1 response, the more severe the disease (44). To delve into the potential mechanism, Cao et al. compared the immune response of T cells in patients with active pulmonary TB and mice treated with MTB and lung cancer cells, and proved that MTB may inhibit Th1 immune response through the programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) signaling pathway. This may lead to Th1/Th2 imbalance and further promote lung cancer metastasis (45). In recent years, studies on the pathogenesis of Tregs in cancer have also attracted the attention of many researchers (41). Tregs can protect tumor cells by inhibiting cytotoxic T lymphocytes (CTL) mediated apoptosis (39, 41, 46). Furthermore, Jie et al. found that Tregs was closely related to the occurrence of TB, and the results showed that the percentage of Tregs in peripheral blood of patients with active TB was significantly higher than that in the latent TB group or control group (Tregs: 11.44 +/- 2.69% vs. 7.54 +/- 1.56% vs. 4.10 +/- 0.99%, p < 0.05) (47). The possible mechanism is that MTB can enhance the polarization ability of Tregs by driving the high expression of BTLA in dendritic cells (48). The increase of Tregs activity can lead to immunosuppression and a decrease in the number of Th1 cells, which are conducive to the occurrence and progression of skin cancer (49). In addition, it has been proved that the production of Tregs and its inhibitory properties can also be regulated through the expression of PD-1 and the binding of PD-1 to PD-L1 (46). For this reason, the treatment of immune checkpoint inhibitors (ICIs) combined with PD-1 or PD-L1, especially for cancers such as non-small cell lung cancer, has shown remarkable efficacy, and may also be of great significance for the treatment of lung cancer caused by TB (46) ( Figure 3 ).

MDSC is a group of heterogeneous cells from bone marrow, which can inhibit immune cell response through reactive oxygen species (ROS) molecules and other pathways, and it has been proved by abundant evidences that it plays an important role in promoting tumor malignant growth and metastasis in tumor immunity (50–53). The reason: On the one hand, in the tumor microenvironment, MDSC exerts an inhibitory effect to produce excess ROS, while MDSC up-regulates the production of ROS in the high-concentration ROS environment. ROS can produce highly destructive hydroxyl radicals, resulting in the damage of DNA, proteins and lipids in the body. At the same time, oncogenes jun and fos are also activated, which eventually lead to the occurrence of tumors under the action of various factors (5, 54–56). On the other hand, in order to maintain an immunosuppressor environment, MDSC secretes a series of chemokines, thereby playing a role in the recruitment of Tregs and thus promoting the development of tumors (41, 46, 57). In addition to its role in tumors, MDSC has gradually been shown to play an important role in many chronic infectious diseases, especially in TB (58). Studies have shown (59) that under abnormal conditions of chronic infections such as TB, excessive production of MDSC will be caused to inhibit host protective T lymphocyte response. The possible mechanisms are as follows: First, MDSC changes the polarization direction of monocytes and macrophages by producing ROS, thereby inhibiting the anti-inflammatory response; On the other hand, studies have shown that MDSC inhibits the immune response of T cells and effector B cells by inducing cells such as Tregs (58). Therefore, it is very possible that MDSC is produced after infection with Mycobacterium TB, and MDSC ultimately promotes the occurrence and development of tumors through up-regulation of ROS and recruitment of Tregs.

Tumor-associated macrophages (TAMs) are one of the major tumor-infiltrating immune cell types and are generally divided into one of two functional contrast subtypes, classically activated M1 macrophages and replacement-activated M2 macrophages. The former usually exerts anti-tumor functions, including directly mediated cytotoxicity and antibody-dependent cell-mediated cytotoxicity (ADCC) to kill tumor cells; the latter promotes the formation and metastasis of tumor cells by inhibiting the anti-tumor immune response mediated by T cells. When the body is exposed to MTB, macrophages play an important role as the main innate immune cells (60, 61). The relevant mechanism of action may be as follows: First, it has been found that IL-37 induces the polarization of macrophages towards M2-like phenotype during MTB infection (62, 63), which may further promote the occurrence and metastasis of tumor cells. Secondly, MTB toxic factor ESAT-6 can drive the polarization of macrophages towards pro-inflammatory M1 phenotype, and subsequently towards anti-inflammatory M2 phenotype, and can also drive the transformation of activated M1 phenotype into M2 phenotype (64), which may play a role in promoting tumor. In addition, in the process of inflammation, activated macrophages will gather at the site of MTB infection and produce a large amount of active nitrogen and ROS, etc. ROS promotes the occurrence and development of tumors by activating oncogenes jun and fos (54, 55). Some scholars used a mouse model infected with MTB to test the effect of macrophage depletion on the occurrence of lung cancer, and the results showed that the incidence of lung cancer in TB mice with macrophage depletion was significantly lower than that in control TB mice without macrophage intervention (65).

EGFR belongs to the ERBB family of tyrosine kinase receptors. The EGFR signaling cascade is a key regulator of cell proliferation, differentiation, division, survival, and cell proliferation, and has been shown to play an important role in regulating the proliferation, survival, and differentiation of tumor cells, and is highly expressed in more than 60% of Nonsmall Cell Lung Cancer (NSCLC) (66). In recent years, more and more researchers have provided evidence that MTB can cause tumors through the EGFR pathway: Nalbandian et al. found that MTB infected macrophages induce the production of highly efficient epidermal regulatory hormone (EREG), thus activating the EGFR signaling pathway through EREG and promoting cancer progression (5, 67). Meanwhile, studies have demonstrated in mouse models that MTB infection can stimulate the expression of EREG in a toll-like receptor 2 (TLR2) -dependent manner, and EREG binds to EGFR in membrane or soluble form to stimulate downstream signal transduction, thereby inducing activation and mutation of k-ras gene, leading to the occurrence of lung cancer (67, 68) ( Figure 4 ).

In addition, EGFR mutations are often directly or indirectly associated with the pathogenesis of some cancers with high global morbidity and mortality, such as lung cancer, pancreatic cancer and head and neck cancer (69–73). Approximately 15% of Caucasian patients and 30%-40% of Asian patients with lung adenocarcinoma carry EGFR mutations (74). Among them, the two major classical mutations are exon 19 deletion and exon 21 L858R mutation, with the incidence of 44% and 41%, respectively (75). EGFR mutations are highly prevalent in tumors, and TB can cause high EGFR mutations. Luo et al. (70) found that patients with lung scar cancer or old TB had a higher incidence of EGFR mutation (p =0.018), especially exon 19 deletion (p<0.001), in patients with lung adenocarcinoma than those without TB focal points. This was also fully demonstrated in a retrospective study of nearly 500 patients with lung adenocarcinoma (76), with a higher frequency of EGFR mutations in the TB group than in the non-TB group (56% vs 34%, p=0.038). A study in Taiwan evaluated the correlation of EGFR mutation outcomes in 275 TB patients (77), with 191 patients (69.5%) having a high EGFR mutation in their study. Although it is certain that TB can induce EGFR mutation and increase the risk of tumor development, the exact molecular mechanism remains to be further elucidated. TB not only affects the mutated status of EGFR, but also affects the treatment response of patients treated with EGFR tyrosine kinase inhibitors (TKIs). At present, EGFR-TKI targeted therapy has become the standard first-line treatment for patients with advanced EGFR-mutated NSCLC, which can significantly improve their prognosis (78). Simultaneous use of antituberculosis drugs and TKIs in a comorbidities patient for EGFR-mutated lung cancer patients with active TB has shown a safe and alternative treatment strategy (79).

Cancer is largely regarded as a disease caused by gene mutation and gene alteration, and the metabolic changes of tumor cells driven by oncogenes can limit the immune response of the body by affecting the tumor microenvironment (TME), thus causing serious adverse effects on the normal immune defense function of the body (80, 81). At present, the mechanism of TB induced by tumor itself is not completely clear. The possible mechanisms are as follows: First, there is a high level of adenosine triphosphate (ATP) in TME, and CD73 decomposes ATP through dephosphorylation, and finally produces adenosine (82). Adenosine has a significant inhibitory effect on immune response (83) and can also play a protective role in extracellular bacteria and fungi, including MTB, by mediating type 3 immune effects (84). In addition, studies on lung cancer patients and mouse models have proved that lung cancer can lead to the loss of microbial diversity, the reduction of the total amount of bacteria and the change of bacterial composition, which can lead to the imbalance of microbial flora, resulting in the reduction of the stability of the body’s immune homeostasis, and thus increase the host’s susceptibility to various pathogens (85, 86). Studies have shown that up to 50%-70% of lung cancer patients are complicated by lung infection during the course of the disease (87). Wessels et al. ‘s study on children showed that the risk of TB among children with malignant tumors was indeed higher than that of ordinary children, and the risk ratio reached 11 times (88).

Platinum-based chemotherapy is recognized as the standard treatment for patients with stage II and III non-small cell lung cancer (NSCLC) and is often considered for stage IB patients with tumors ≥4cm (87). Chemotherapy drugs have an effective killing effect on tumor cells, but they also affect the immune system of patients. Investigation in TB endemic areas found that TB infection was common in systemic chemotherapy (89). On the one hand, chemotherapy can produce immunosuppressive effects on cellular immunity and immunoglobulin, affecting the normal immune function of patients. Chemotherapy, on the other hand, can cause neutropenia and leukopenia by inhibiting bone marrow function, leading to a state of severe immune deficiency with symptoms such as cough, hypoxia, dyspnea, and fever. In addition, although chemotherapy-induced pulmonary toxicity is rare in clinical practice, it can be manifested as hypersensitivity reaction, interstitial pneumonia, non-cardiogenic pulmonary edema, pleural effusion, obliterated bronchiolitis, tissue pneumonia and progressive pulmonary fibrosis. The above diseases all affect the normal immune defense function of the normal lung, thereby increasing the susceptibility of the lung to bacteria including MTB (90). Clinically, there have been reports of patients with non-small cell lung cancer infected with MTB after receiving standard chemotherapy based on bisplatin and pulmonary TB during postoperative chemotherapy for gastric cancer (91, 92). Another study, which recruited 1,809 cancer cases and 1,809 control subjects and followed them for 3 years, showed that immunosuppression of cancer or anti-cancer chemotherapy increased the risk of TB reactivation, especially in cancer patients with age-cured TB (93).

As new immune checkpoint inhibitors continue to enter clinical trials, ICIs is becoming one of the most important immunotherapy therapies. lCIs mainly inhibits immune checkpoint proteins by blocking CTLA-4, PD-1 and PD-L1. At present, immunotherapy of PD-1/PD-L1 has significantly prolonged the survival of patients with advanced lung cancer, and has become the standard treatment choice for the first and second line of advanced lung cancer (94). However, when ICIs are selected, they also affect immune function, which may increase susceptibility to MTB infection. There are two possible reasons for this: First, because ICIs works by blocking CTLA-4, PD-1, and PD-L1 to inhibit immune checkpoint proteins, model studies in knockout mice have demonstrated that conditions in which CTLA-4 and PD-1 are absent may lead to imbalanced immune homeostasis, resulting in reduced host immunity (95–97). Studies have shown that immunocompromised people with latent infections have a higher rate of active TB. Therefore, ICIs leads to a decrease in the body’s immunity, which may be one of the reasons for an increased susceptibility to MTB infection. In addition, pneumonia caused by ICIs is the most common pulmonary toxic reaction, which may also be one of the reasons for the increased susceptibility to MTB infection (98–100). Macrophage apoptosis plays an important role in pneumonia. Through the mutual influence and stimulation of inflammation and apoptosis, the apoptosis of macrophages is accelerated while the inflammation is aggravated (101). After MTB enters the body through the respiratory tract, the body mainly plays a defense role through macrophages and other cells. Therefore, apoptosis of macrophages increases the risk of TB and latent TB reactivation. Through comparative analysis of the function of macrophages at different stages of pneumonia in mice, it was found that macrophages’ ability to phagocytic bacteria was still poor several weeks after the inflammation subsided (102).