Research progress on lung cancer complicated with pulmonary tuberculosis: a narrative review

Introduction

Lung cancer (LC) represents a significant public health problem. In 2022, there were 1.06 million new LC cases and 733,000 LC-related deaths in China, which ranks first among all kinds of malignant tumors in terms of both incidence and mortality (1). There are two main types of LC: small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). In the last two decades, the 5-year survival rate of NSCLC has been less than 20%, while that of SCLC is close to 5% (2). Tuberculosis (TB) is another significant public health problem caused by Mycobacterium tuberculosis (M. tuberculosis) (3). M. tuberculosis can spread through droplets in the human population, causing life-threatening lung disease in the immune host (4). In 2022, there were approximately 748,000 new TB cases and 30,000-TB related deaths in China (5).

It has indicated that M. tuberculosis infection can cause LC (4), and the development and treatment of LC may also make LC patients susceptible to TB and secondary TB infection or stimulate the reactivation of latent TB infection. LC patients with TB have a worse prognosis and are more challenging to treat than LC patients without TB. Thus, it is of great significance to study the relationship between LC and TB, as well as how to manage co-existing TB and LC. We present this article in accordance with the Narrative Review reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-450/rc).

Methods

Study search methods

In this review, the inclusion criteria for literature research were (I) from the PubMed/MEDLINE database; (II) retrospective cohort studies, observational studies, systematic reviews, and meta-analyses; (III) published between the database’s inception and 2024; (IV) with the keywords “tuberculosis” and “lung cancer”; (V) language was Chinese or English. Unpublished papers or non-full-text articles were excluded (Table 1). Also, we conducted manual searches of the reference lists of the retrieved articles to identify relevant articles.

Pathogenesis of comorbidity between pulmonary tuberculosis (PTB) and LC

PTB and LC have a complex reciprocal promotion connection that might lead to comorbidity when multiple factors affect their occurrence and development.

PTB as a risk factor for LC

TB can promote the occurrence of lung squamous cell carcinoma, lung adenocarcinoma, and SCLC (6). A study of TB in Taiwan found that about a quarter of LC patients also had latent TB infection (7). Liang et al. (8) performed a meta-analysis of 37 case-control and four cohort studies to assess the association between the risk of LC and pre-existing TB and found that the risk of LC was highest within 5 years of TB diagnosis [relative risk (RR) =11.15; 95% confidence interval (CI): 7.57–16.41], but the risk of LC remained 1.99-fold elevated for more than 20 years after TB diagnosis. Leung et al. (9) performed a meta-analysis of 52,480 cancer patients from 49 studies and found that TB was associated with LC (RR =1.7; 95% CI: 1.5–2.0). The meta-analysis of Sodeifian et al. (10) of nine cohort studies and 28 case-control studies also provides strong evidence of an increased risk of LC after PTB. They found a significant association between prior PTB and LC in both the cohort [odds ratio (OR) =2.3; 95% CI: 1.4–3.8] and case-control (OR =1.9; 95% CI: 1.4–2.5) studies. However, some studies have reached indeterminate conclusions. For example, Ramanakumar et al. (11) conducted two case-control studies in the Canadian population to analyze the possible relationships between a previous history of lung disease and subsequent risk of LC. For the association between TB and LC, the evidence was inconsistent between Study I (interviewed in 1979–1986) and Study II (interviewed in 1996–2001). Since observational research designs cannot determine the causal sequence, Mendelian randomization (MR) approaches emerged to reduce these issues. A latest MR study suggested that TB is a risk factor for LC at a genetically predicted level, potentially mediated through immune cell and metabolite regulation (12).

Besides, Cabrera-Sanchez et al. (13) conducted a systematic review of 29 cohort and 44 case-control studies to evaluate the association between TB and subsequent LC occurrence and mortality and found that the occurrence [hazard ratio (HR) =5.01; 95% CI: 3.64–6.89] and mortality (HR =1.62; 95% CI: 1.18–2.21) of LC increased after TB diagnosis. A retrospective cohort study of 42,422 farmers was conducted to evaluate the association between PTB and subsequent LC mortality (14). The results showed that the mortality rate of the LC patients with a history of TB (25/1,000 person-years) was higher than that of the patients without a history of TB (3.1/1,000 person-years), especially during the first 5 years after the diagnosis of PTB, and remained stable for 5–9.9 years (HR =3.4; 95% CI: 1.3–9.1) and more than 10 years (HR =3.0; 95% CI: 1.3–7.3).

Nevertheless, the association of TB with LC may be confounded by multiple confounding factors, such as air pollution, smoking, alcohol misuse, human immunodeficiency virus (HIV), and socioeconomic disadvantages (15,16). These variables were not controlled by most of the studies included in our review and could impart residual confounding on the risk of cancer in the TB population. Traditional observational studies have difficulty in determining causal relationships and cannot avoid selection bias. Although some common confounding factors are avoided in the MR study, these causal relationships may also be influenced by genetic characteristics in people with different races. Also, cancer may be misdiagnosed as TB both clinically and radiographically (17), and the definitions of active TB often be different. Herein, future prospective studies are supposed to include the timing and staging of cancer in their analysis, and pre- and post-treatment imaging diagnosis information trying to avoid confounders in association between TB and LC.

Mechanism under associations between PTB and LC

It has been hypothesized that M. tuberculosis infection causes LC via chronic inflammatory stimulation, scar formation, DNA damage, or immune dysfunction (Figure 1). Chronic inflammation can create a tumor microenvironment conducive to tumor growth and progression. M. tuberculosis can cause inflammation in lung tissues by secreting inflammatory cytokines such as interferon-gamma (INF-γ), tumor necrosis factor (TNF), and interleukins (18,19). Tumor occurrence and development are closely linked to cell hyperplasia and apoptosis. In particular, inflammatory factors related to cell hyperplasia and apoptosis play a significant role in the occurrence and development of tumors. TNF and interleukin-6 promote anti-apoptotic gene expression in pulmonary epithelial cells via the nuclear factor kappa B pathway, contributing to cancer progression (20,21). However, the exact molecular mechanism of tumors caused by inflammatory factors still needs further exploration.

Figure 1 PTB is a risk factor for LC. PTB may cause LC via various pathways, including chronic inflammatory stimulation, scar formation, and DNA damage. LC, lung cancer; PTB, pulmonary tuberculosis.

TB is a chronic infection process accompanied by lung tissue remodeling. Following TB infection, an aggressive immune response occurs, which may result in the development of granulomas in the lungs. Alveolar macrophages engulf invasive M. tuberculosis and sequester it in the phagosome, which is surrounded by myeloid cells and lymphocytes. Antigen-specific T lymphocytes produce INF-γ and other cytokines. Activated macrophages create more inflammatory cytokines, reactive oxygen species (ROS), prostaglandins, and proteases to eliminate the bacteria. This inflammatory injury and the subsequent repair process of lung epithelial cells result in a fibrous scar and, ultimately, extensive pulmonary fibrosis. Scar carcinomas are most likely caused by an inflammatory process in scar tissue (22).

M. tuberculosis lesions are severely hypoxic, which promotes the expression of matrix metallopeptidase 1 (MMP1) in lung epithelial cells and macrophages. MMP1 expression causes hypoxia-inducible factor 1 alpha accumulation in TB granulomas and increases collagenase activity, resulting in lung destruction and cavitation (23). M. tuberculosis can exacerbate oxidative stress in the peripheral circulation, causing DNA damage. Over time, the accumulation of DNA damage leads to gene mutations and tumors (24). M. tuberculosis infection upregulates ROS and nitric oxide levels in macrophages (25) and alveolar epithelial cells (26). Excessive ROS produced by inflammatory cells contribute to the destruction of M. tuberculosis as a fundamental host defensive mechanism. However, ROS activation can also cause biological events, such as the reaction to DNA damage, mitochondrial dysfunction, apoptosis inhibition, and signal transduction limitation, leading to tissue damage, delayed wound healing, and fibrosis (27,28). In addition, increased ROS release leads to the increased expression of the oncogenes jun and fos (29,30). Jun/fos activation promotes cell proliferation by suppressing cyclin-dependent kinase inhibitor 1A (P21) expression, resulting in second gap (G2)/mitotic period (M) cycle arrest and progression to mitosis (31,32). P21 also binds to cyclin-dependent kinases, which inhibit the progression from G0 to the first gap (G1) and G1 to the synthesis phase (S phase) (33). These changes in the cell cycle not only increase the rate of cell division but also shorten the time of DNA repair while reducing the time of apoptosis onset, damage onset, and existing mutation onset in dividing cells with DNA damage, significantly increasing the risk of carcinogenesis.

In conclusion, M. tuberculosis-induced chronic inflammation may have a role in the development of LC via chronic inflammatory stimulation, scar formation, and DNA damage.

LC leads to the reactivation of TB

LC may promote TB infection or lead to the reactivation of latent TB infection (34). Many studies have reported a higher prevalence of active PTB among LC patients (14,35-37). Suzuki et al. (35) conducted an observational study of 904 consecutive patients diagnosed with histologically confirmed LC from March 2007 to March 2013. They followed up with the patients until March 2015 (mean follow-up time: 25.2 months). They reported that during the observation period, 9 LC patients (1.00%) acquired TB. In all cases, TB occurred within 2 years of the diagnosis of LC. The cumulative incidence of TB at 6 months, 1 year, and 2 years was 0.65%, 1.15%, and 1.38%, respectively (35).

TB recurrences are more common in patients with hematologic malignancies than in those with solid tumors (36). LC has the most remarkable TB reactivation rate among solid tumors, followed by gastric cancer, breast cancer, liver cancer, and colon cancer (36). Wu et al. (37) conducted a retrospective cohort study of 16,487 cancer patients and 65,948 controls to investigate the incidence of TB among cancer patients. The incidence of TB per 100,000 person-years was 339 in cancer patients and 202 in controls (HR =1.64; 95% CI: 1.24–2.15).

Malnutrition, cancer-related immune deterioration, and the administration of chemotherapy or radiotherapy are all likely to contribute to TB infection or reactivation (7,36). The majority of research shows that concurrent or sequential active TB has a negative effect on LC prognosis. In a large retrospective cohort study in Xuanwei, China, Engels et al. (17) found that LC patients with TB had a significantly higher mortality rate than those without TB (HR =6.1; 95% CI: 4.3–8.7). Thus, it is essential to promptly diagnose and control the TB infection when LC is diagnosed.

The diagnostic challenge of co-existent LC and TB

The clinical manifestations and imaging features of LC and TB may overlap; thus, the co-existence of the two conditions increases the risk of missed diagnosis and misdiagnosis. The gold standard for diagnosing LC is a pathological examination. Both bronchoscopy and percutaneous lung biopsy are helpful in the early diagnosis of LC. The liquid biopsy technique is considered one of the most promising future methods for LC screening and early diagnosis because of its rapidity, simplicity, and non-invasiveness advantages. LC autoantibodies, circulating tumor cells, circulating tumor DNA (ctDNA), ctDNA methylation, exosomes, and complements are helpful for the early screening and diagnosis of LC. However, these strategies have not been validated in large sample-size clinical trials and require further verification.

The gold standard for the diagnosis of TB is the detection of M. tuberculosis in standard samples of patients with TB. The classic microbiologic indicators of TB in clinical practice are microscopic direct smear positivity of acid-fast bacilli (AFB), the culture and identification of the M. tuberculosis complex, and the nucleic acid amplification of M. tuberculosis. Ziehl-Nisl (Z-N) acid-fast staining and fluorine staining methods are widely used to detect M. tuberculosis in smears. The minimum detection limit of the Z-N method is 5×10³–5×10⁴ CFU/mL. At the same time, the minimum detection limit of the culture method is 10–100 CFU/mL. As the sensitivity of the culture method is higher than that of the smear, it cannot be replaced by the smear. The application of polymerase chain reaction (PCR) assays in diagnosis is becoming increasingly widespread. PCR is highly sensitive, requiring only five purified M. tuberculosis gene fragments in sputum or bronchoalveolar lavage fluid to obtain a positive result. If the nucleic acid is positive, further primers and probes are designed for the 81 bp rifampin (RFP) resistance core region of the rpoB gene to detect the mutation (38).

Treatment of co-existing LC and TB

Both LC and TB have established and systematic treatment strategies; however, when LC and TB coexist, the disease specialty of the first attending physician can easily lead to neglect and delayed treatment of the other disease due to missed diagnoses and misdiagnoses. After confirming the diagnosis of comorbidities, there is still no clear consensus as to the timing of the interventions, the mutual influence and adverse reactions between the two drug treatments, and the survival benefits. Early screening and diagnosis, as well as the combined therapy of LC and TB, are critical in the diagnosis and treatment of patients with these comorbidities. Figure 2 shows an algorithm for the treatment of co-existing TB and LC.

Figure 2 The algorithm for the treatment of co-existent PTB and LC. AFB, acid-fast bacilli; esp., especially; ICI, immune checkpoint inhibitor; LC, lung cancer; NSCLC, non-small cell lung cancer; PCR, polymerase chain reaction; PTB, pulmonary tuberculosis; TB, tuberculosis.

Surgery

Surgery is still the first option for early-stage NSCLC. At the initial diagnosis of early-stage LC, concomitant PTB can be diagnosed by a positive sputum AFB smear or TB-PCR from respiratory specimens. Patients with LC and active TB who have surgical indications should elect to undergo surgical treatment as soon as possible after a negative sputum smear. Perioperative anti-TB treatment does not increase the operative risk, such as delayed surgery and difficult intraoperative excision. In smear-positive PTB, a 2-week combination of isoniazid, RFP, pyrazinamide, and streptomycin reduces the number of M. tuberculosis colony units in sputum by threefold (39). According to research, preoperative anti-TB treatment for 2 to 3 weeks and postoperative anti-TB therapy for at least 6 months can effectively prevent postoperative TB recurrence, bronchopleural fistula, and other complications (38). If the postoperative pathology is granulomatous inflammation, the resected specimen should be stained with AFB and cultured. The need for anti-TB treatment is based on radiological evidence of active disease, microbiological evidence of TB, and the requirement for chemotherapy.

Chemotherapy

Anti-cancer chemotherapy is administered with third-generation platinum-based regimens for NSCLC and cisplatin plus etoposide for SCLC. The majority of first-line anti-TB drugs are not toxic-enhancing and compatible when combined with LC chemotherapy (40,41). Kim et al. (42) reported that anti-cancer chemotherapy does not impede the treatment of TB in cancer patients (in the study, the LC patients accounted for 8% of the subjects). Chai et al. (43) conducted a retrospective cohort study to evaluate the adverse effects of concurrent chemotherapy and anti-TB therapy. They found no serious adverse effects related to anti-TB treatments. The most common side effect in the TB treatment group was liver injury, most cases of which were non-serious and successfully treated with appropriate interventions. These findings suggest that anti-TB treatments can be administered to LC patients with active TB. However, some anti-TB and anti-cancer chemotherapy drugs can cause liver function damage. Thus, during chemotherapy, anti-TB drugs with lower liver toxicity should be used. During combined therapy, liver and kidney function, blood routine, and gastrointestinal reactions should be monitored closely (43). Concomitant anti-TB, preoperative neoadjuvant, and postoperative adjuvant chemotherapy do not increase the risk of abnormal liver and kidney function, abnormal blood routine, and severe gastrointestinal reactions.

Immunotherapy

Immune checkpoint inhibitors (ICIs) are a novel treatment modality extensively studied in recent years. Combination ICI therapy with or without chemotherapy may improve the survival of LC patients (44). However, there is growing evidence that programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) immunotherapy has a significant effect on the incidence and mortality of TB in cancer patients (45). The effects of the PD-1 and PD-L1 signaling pathways on the immune system response to M. tuberculosis are complex. Further research is required to investigate the molecular mechanism of TB development following ICI treatment. Currently, immunotherapy is not recommended for sputum-positive PTB.

Targeted therapy

Targeted drugs are less toxic and have fewer side effects than chemotherapy (46,47). Generally, targeted drug therapy is combined with anti-TB treatment. Targeted drugs also have limitations when used concurrently with TB therapy. Cytochrome P450 3A4 (CYP3A4) induced by RFP can reduce blood drug concentrations by increasing the metabolism of targeted drugs such as gefitinib, erlotinib, crizotinib, and alectinib (48). RFP should be changed to rifabutin to avoid decreasing the blood concentration of molecularly targeted drugs (48). The incidence of grade 3 liver dysfunction induced by epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors is approximately 1.7–18%, and RFP should be excluded from anti-TB therapy in LC patients with EGFR mutations due to drug metabolism and potential interactions (46). Alternatively, drugs metabolized by bile, such as afatinib, could be selected (49).

Radiotherapy

Previously, patients with LC and PTB have had relatively low autoimmunity, and excessive radiotherapy reduces anti-TB efficacy and even causes dissemination. LC with active PTB was once considered a contraindication to radiotherapy. However, as people’s living standards have improved, so have patients’ immune systems. Ino et al. (50) reported that a patient with LC and PTB received conventional radiotherapy during hospitalization, followed by outpatient chemotherapy for 2 years to achieve long-term survival. Xie et al. (51) collected the data from 18 patients with PTB and LC who were treated with radiotherapy between September 1996 and July 1999 and found that none of these patients had disseminated TB. This phenomenon is considered to be related to supportive treatment and anti-TB treatment before and after treatment. More research is needed on radiotherapy for patients with active TB complicated by tumors. Radiotherapy treatment should include pre- and post-treatment support, as well as anti-TB therapy.

Conclusions

Chronic inflammation, fibrosis, and DNA damage caused by TB are associated with the development and progression of LC. LC may also reactivate TB. LC and TB mutually promote each other. The causal association between TB and LC still needs to be clarified through multicenter and large-sample prospective studies with populations with different characteristics. The fundamental principle of patient management is to balance anti-tumor and anti-TB treatments based on the patient’s physical condition and make comprehensive intervention decisions. Currently, there is no standard diagnosis and treatment plan for LC-TB, and therefore, searching for biomarkers related to the diagnosis of LC-TB and the validation of potential diagnostic tools will be a topic of great significance, and is also a critical clinical issue that urgently needs to be addressed.

In terms of diagnosis, clinical doctors should pay attention to suspected symptoms and imaging manifestations of comorbidities in patients with uncomplicated LC/TB and promptly conduct pathogen and/or pathological tests to confirm the diagnosis. Regarding treatment, current reports mainly focus on case studies, and some conclusions need to be confirmed through more extensive research. In the future, clinical research on LC-TB as the object of study is urgently required to provide a more scientific basis for the potential pathogenesis between TB and LC, as well as the rational diagnosis and treatment of comorbidities. Research also needs to be conducted to ensure the early screening and diagnosis of LC-TB, the concurrent management of LC and TB, and the precise diagnosis and therapy of LC and TB.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-450/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-450/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2025-450/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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(English Language Editor: L. Huleatt)