Lung cancer is one of the most dangerous malignant tumors to human health and life in the world today, and the incidence and mortality of lung cancer have been increasing significantly in recent years, seriously threatening human health. Although comprehensive treatment programs such as surgery, chemotherapy and radiotherapy have been applied clinically in combination, the five-year survival rate of lung cancer patients is still not high, and there is an urgent need to find new treatment pathways and methods to eradicate or control lung cancer. Tumor stem cell theory suggests that tumor is a stem cell disease, and the few tumor stem cells with self-renewal and unlimited proliferation ability are the root cause of tumor occurrence or recurrence. This paper provides a comprehensive analysis of the latest research on lung cancer stem cells and potential drug research targeting tumor stem cells, which provides new ideas for lung cancer treatment and research. A large number of theories and experiments now suggest that tumor stem cells may be closely related to drug resistance. Similar to normal stem cells, the slow growth and mostly dormant state contribute to the development of drug resistance in tumor stem cells. In addition, tumor stem cells are highly expressed with various ABC transporter proteins on their surface, such as ABCB1 gene encoding P2 glycoprotein, ABCG2/MXR gene encoding multidrug resistance-associated protein 1 (MRP1) and breast cancer resistance protein 2 (bcl-2), which have the ability to efflux drugs and toxicants. ABCG2, ABCB1 or ABCC1 knockout mice are more sensitive to drugs such as perphenazine, isoavanomycin and mitoxantrone, suggesting that the ABC transporter protects cells from chemotherapeutic drugs, or perhaps after the accumulation of genetic mutations, tumor stem cells inherit this multidrug resistance mechanism; or the presence of genetic mutations or abnormal differentiation leads to the development of multidrug resistance in recurrent tumors. This would explain why otherwise non-resistant tumors acquired multidrug resistance after chemotherapy relapse. sung et al. also found that the lateral population cell subpopulation of A549 cell line had high expression of ABCG2 gene and high expression of MDR1 and ABCC2 genes, and demonstrated their association with tumor drug resistance. Lung cancer stem cells and lung cancer recurrence Lung cancer conventional treatment options, such as radiotherapy and chemotherapy, are widely used for various malignancies, including lung cancer, but these tools are often effective in the initial stage of treatment but have a short maintenance time and are associated with recurrence. The target cells killed by radiotherapy are actively proliferating lung cancer cells or targeted precursor cells, while dormant lung cancer stem cells are often in G0 stage, which are insensitive to radiation and chemical drugs and can resist the killing by radiotherapy and become the source of recurrence later, which may be the reason for the failure of current treatment for malignant tumors. Therefore, treatment targeting tumor stem cells may have longer-lasting effects, and targeted removal of lung cancer stem cells would be a new breakthrough point in the treatment of lung cancer. Potential tumor stem cell targeting drugs The principle of tumor stem cell targeting drugs is to inhibit the signal transduction pathways of tumor stem cell self-renewal and proliferation, including Wnt/β-catenin, SHH, Notch, PI3K/PTEN/AKT, and also to reverse the drug resistance of tumor stem cells by blocking ABC transporter protein, which can be used together with other chemotherapeutic drugs. The therapeutic effect can also be achieved by blocking ABC transporter proteins to reverse the resistance of tumor stem cells. Alternatively, small molecule inhibitors such as RNAi technology can be used to block the activation of these signaling pathways to treat tumors. There are several drugs that can affect the self-renewal of tumor stem cells or alter their microenvironment by acting on certain pathways. gamma protein secretase inhibitors can target the Notch pathway to inhibit the growth of leukemia and lymphoma cells. Improving the microenvironment of tumor stem cells, especially angiogenesis. Bevacizumab, an anti-vascular endothelial growth factor monoclonal antibody, has been shown to be effective in the treatment of colon cancer. Anti-angiogenic therapy has been applied in the treatment of non-small cell lung cancer and has resulted in survival benefits for patients. Direct targeting of lung cancer stem cells, identifying lung cancer stem cells based on specific surface molecular markers, preparing monoclonal antibodies, carrying radioactive substances or chemotherapeutic drugs, and directly targeting radiotherapy ultimately induces apoptosis of lung cancer stem cells and deprives the tumor of the ability to generate new tumor cells, striving for radical cure. Targeted killing is performed through molecular antigens on the surface of tumor stem cells. Now in clinical use, gibberellin/ozomicin is a coupling of a humanized anti-CD133 monoclonal antibody and the cytotoxic antitumor antibiotic spinosporin for the treatment of relapsed acute myeloid leukemia (AML). The anti-CD44 monoclonal antibody was recently found to eliminate AML stem cells. Lycopene is a naturally occurring compound extracted from young sprouts of green cauliflower or Cauliflower. Its antitumor efficacy is mentioned to be confirmed in different tumors. For example, oral or intravenous administration of lycopene inhibited tumor growth in prostate cancer PC-3 and pancreatic cancer Panc-1 graft. The risk of premenopausal breast cancer can be reduced in humans by oral lysostaphane, which increases the activity of detoxifying enzymes after reaching the breast. In addition, lysostaphane has the potential to reverse tumor resistance and recurrence. In a recent study, lysostaphane was shown to effectively block tumor resistance in pancreatic cancer by inducing ligands that interfere with the NF-κB anti-apoptotic pathway and cause TNF-α-related apoptosis. Another study implied that lycopene reversed the induction of apoptosis in doxorubicin-resistant restored cells. Recent studies have shown that lycopene effectively inhibits breast cancer stem cells, with high inhibition efficiency even at lower drug concentrations. More importantly, the inhibitory effect of lysostaphane on tumor stem cells after treatment with lysostaphane persisted even after the drug exposure was removed. The mechanism by which lysostaphane inhibits breast cancer stem cells is known to be through the inhibition of the activation of Wnt/β-catenin signaling pathway. As an excellent chemical drug for targeting tumor stem cells, the mechanism of action of lysostaphane still needs to be further investigated. Another food-derived compound is the polyphenolic leucovorin, which is found in a variety of plants, including grapes, peanuts, and many different herbal medicines. Studies have shown that leucovorin has anti-inflammatory, antioxidant, antitumor, neuroprotective, and immunomodulatory activities. Leucovorin modulates a variety of signaling pathways associated with tumorigenesis and development. Its antitumor activity in pancreatic cancer includes inhibition of tumor cell proliferation and angiogenesis and induction of apoptosis. Leucovorin increases the antitumor activity of gemcitabine in vitro and in pancreatic cancer in situ tumors. Recent studies have shown that albuterol enhances the therapeutic potential of antitumor drugs and increases the sensitivity of tumor cells to chemotherapy and radiotherapy. Recent studies also suggest that leucovorin can effectively inhibit pancreatic cancer stem cells in human or transgenic mice by inhibiting multipotency factors and EMT in tumor cells. It has a synergistic effect when co-treated with lycopene on tumor stem cells. In addition, renowned American oncologist Weinberg and his team screened a drug from 16,000 chemicals that can effectively inhibit breast cancer tumor stem cells, Salinomycin, called salinomycin in Chinese, and proved that it is 100 times more effective in killing breast cancer stem cells in mice than the common anti-cancer drug, Taxol. Salinomycin not only kills breast cancer stem cells in mice, but also inhibits them from producing new tumor cells and slows the growth of existing tumors, as reported in the 2009 issue of Cell. Salinomycin is a polyether monocarboxylic acid with molecular formula C42H69O11Na and molecular weight 772.99. It is produced by the fermentation of Streptomyces albus and has a special ring structure, which is a typical ion-carrier antibiotic, and its affinity for cations in cells, especially K+ and Na+, is particularly strong, which enhances the permeability of biologically essential cations through the lipid barrier on the membrane It is a typical ion-carrier antibiotic, which has a strong affinity for cations in cells, especially K+ and Na+, and enhances the permeability of cations necessary for living organisms through the lipid barrier on the membrane.