Co-inhibition of TIGIT and PD-1/PD-L1 in Cancer Immunotherapy: Mechanisms and Clinical Trials.

Over the past decade, immune checkpoint inhibitors (ICIs) have emerged as a revolutionary cancer treatment modality, offering long-lasting responses and survival benefits for a substantial number of cancer patients. However, the response rates to ICIs vary significantly among individuals and cancer types, with a notable proportion of patients exhibiting resistance or showing no response. Therefore, dual ICI combination therapy has been proposed as a potential strategy to address these challenges. One of the targets is TIGIT, an inhibitory receptor associated with T-cell exhaustion. TIGIT has diverse immunosuppressive effects on the cancer immunity cycle, including the inhibition of natural killer cell effector function, suppression of dendritic cell maturation, promotion of macrophage polarization to the M2 phenotype, and differentiation of T cells to regulatory T cells. Furthermore, TIGIT is linked with PD-1 expression, and it can synergize with PD-1/PD-L1 blockade to enhance tumor rejection. Preclinical studies have demonstrated the potential benefits of co-inhibition of TIGIT and PD-1/PD-L1 in enhancing anti-tumor immunity and improving treatment outcomes in several cancer types. Several clinical trials are underway to evaluate the safety and efficacy of TIGIT and PD-1/PD-L1 co-inhibition in various cancer types, and the results are awaited. This review provides an overview of the mechanisms of TIGIT and PD-1/PD-L1 co-inhibition in anti-tumor treatment, summarizes the latest clinical trials investigating this combination therapy, and discusses its prospects. Overall, co-inhibition of TIGIT and PD-1/PD-L1 represents a promising therapeutic approach for cancer treatment that has the potential to improve the outcomes of cancer patients treated with ICIs.

Optimal timing and sequence of combining stereotactic radiosurgery with immune checkpoint inhibitors in treating brain metastases: clinical evidence and mechanistic basis.

Recent evidence has shown that immune checkpoint inhibitors (ICIs) are efficacious for treating brain metastases of various primary tumors. However, the immunosuppressive tumor microenvironment and the blood-brain barrier (BBB) or blood-tumor barrier (BTB) essentially restrict the efficacy of ICIs. Stereotactic radiosurgery (SRS) can be a powerful ally to ICIs due to its trait of disrupting the BBB/BTB and increasing the immunogenicity of brain metastases. The combination of SRS + ICI has shown synergy in brain metastases in several retrospective studies. Nevertheless, the optimal schedule for the combination of SRS and ICI in brain metastases is yet to be determined. In this review, we summarized the current clinical and preclinical evidence on the timing and sequence of SRS + ICI to provide insight into the current state of knowledge about this important area in patient care.

Resistance mechanisms to osimertinib and emerging therapeutic strategies in nonsmall cell lung cancer.

PURPOSE OF REVIEW: This review aims to introduce the resistance mechanisms to osimertinib, discuss the therapeutic strategies, and make clinical updates in overcoming resistance to osimertinib. RECENT FINDINGS: Osimertinib has shown favorable efficacy on second-line and first-line treatments in EGFR-mutant advanced nonsmall cell lung cancer (NSCLC). However, the presence of primary and acquired resistance to osimertinib restricts its clinical benefits. The primary resistance mainly consists of BIM deletion polymorphism and EGFR exon 20 insertions. Meanwhile, the heterogeneous mechanisms of acquired resistance include EGFR-dependent (on-target) and EGFR-independent (off-target) mechanisms. EGFR C797S mutation, MET amplification, HER2 amplification, and small cell lung cancer transformation were identified as frequent resistance mechanisms. Recently, more novel mechanisms, including rare EGFR point mutations and oncogenic fusions, were reported. With the results of completed and on-going clinical trials, the emerging therapeutic strategies of postosimertinib progression are summarized. SUMMARY: The resistance mechanisms to osimertinib are heterogeneous and gradually perfected. The combination of osimertinib with bypass targeted therapy and other therapeutic approaches emerge as promising strategies.

Adjuvant EGFR tyrosine kinase inhibitors for patients with resected EGFR-mutated non-small-cell lung cancer: a network meta-analysis.

Aim: To investigate the efficacy and safety of adjuvant EGFR tyrosine kinase inhibitors for resected EGFR-mutated non-small-cell lung cancer. Materials & methods: Eligible phase II/III randomized controlled trials were included for the network meta-analyses (PROSPERO CRD42021275150). Results: Nine records and 831 patients were involved. Adjuvant chemotherapy followed with osimertinib significantly prolonged disease-free survival compared with chemotherapy (hazard ratio [HR]: 0.2; 95% CI: 0.14-0.29), chemotherapy followed with erlotinib (HR: 0.33; 95% CI: 0.18-0.6), chemotherapy followed with gefitinib (HR: 0.36; 95% CI: 0.16-0.82), gefitinib (HR: 0.26; 95% CI: 0.17-0.41) and icotinib (HR: 0.56; 95% CI: 0.3-0.98). Icotinib was the least likely to cause grade ≥3 adverse events. Conclusion: Chemotherapy followed with osimertinib brings about the best disease-free survival. Icotinib monotherapy shows the best safety.

Patients with early-stage non-small-cell lung cancer have about a one in five chance of cancer recurrence, even after complete resection. Using agents targeting EGFR, known as adjuvant EGFR tyrosine kinase inhibitors, after surgery is an effective way for patients with EGFR-mutated non-small-cell lung cancer to prevent recurrence. However, the optimal agent with favorable efficacy and safety is yet to be determined. This study showed that adjuvant chemotherapy followed with osimertinib had the best efficacy, while adjuvant icotinib monotherapy had the best safety.

Influence of spiral framework on nonlinear optical materials.

A series of spiral donor-π-acceptor frameworks (i.e. 2-2, 3-3, 4-4, and 5-5) based on 4-nitrophenyldiphenylamine with π-conjugated linear acenes (naphthalenes, anthracenes, tetracenes, and pentacenes) serving as the electron donor and nitro (NO2 ) groups serving as the electron acceptor were designed to investigate the relationships between the nonlinear optical (NLO) responses and the spirality in the frameworks. A parameter denoted as D was defined to describe the extent of the spiral framework. The D value reached its maximum if the number of NO2 groups was equal to the number of fused benzene rings contained in the linear acene. A longer 4-nitrophenyldiphenylamine chain led to a larger D value and, further, to a larger first hyperpolarizability. Different from traditional NLO materials with charge transfer occurring in the one-dimensional direction, charge transfer in 2-2, 3-3, 4-4, and 5-5 occur in three-dimensional directions due to the attractive spiral frameworks, and this is of great importance in the design of NLO materials. The origin of such an enhancement in the NLO properties of these spiral frameworks was explained with the aid of molecular orbital analysis.

Efficacy and safety of personalized optimal PD-(L)1 combinations in advanced NSCLC: a network Meta-Analysis.

INTRODUCTION: Programmed death 1 (PD-1)/programmed death 1 ligand 1 (PD-L1)-directed immunotherapy has revolutionized the treatments for advanced non-small cell lung cancer (NSCLC), whereas the optimal therapeutic combinations remain uncertain. METHODS: Our study encompassed phase Ⅱ/III randomized controlled trials (RCTs) that involved anti-PD-(L)1-based therapies for stage-IV NSCLC. The primary outcomes included overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and incidences of adverse events (AEs). Subgroup analyses were conducted by treatment lines, PD-L1 expression levels, histological types, and metastatic sites. RESULTS: Our analysis incorporated 38 publications, covering 14 therapeutic combinations and involving 18,048 participants. PD-(L)1+chemotherapy (CT), PD-(L)1+ cytotoxic T lymphocyte-associated antigen-4 (CTLA4) +CT, and PD-(L)1+ T-cell immunoglobulin and ITIM domain (TIGIT) were notably effective in prolonging OS. Overall, PD-(L)1+CT and PD-(L)1+CT+ vascular endothelial growth factor (VEGF) were significantly beneficial for PFS and ORR. As for the subsequent-line treatments, incorporating radiotherapy can enhance PFS and ORR (ranked fourth among enrolled treatments). For patients with PD-L1 < 1%, PD-(L)1+CT+VEGF and PD-(L)1+CTLA4+CT were favorable approaches. Conversely, in patients with PD-L1 ≥ 50%, PD-(L)1+CT represented an effective treatment. Patients with non-squamous cell carcinoma or liver metastases might benefit from the addition of VEGF. In cases of squamous cell carcinoma or brain metastases, the combination of PD-(L)1+CTLA4+CT yielded superior benefits. CONCLUSIONS: This study underscores the enhanced efficacy of combination immunotherapies over monotherapy. It highlights the necessity for personalized treatment, considering individual factors. These insights are vital for clinical decision-making in the management of advanced NSCLC.

First-line treatments for advanced non-squamous non-small cell lung cancer with immune checkpoint inhibitors plus chemotherapy: a systematic review, network meta-analysis, and cost-effectiveness analysis.

Introduction: The combination of immune checkpoint inhibitors (ICIs) and chemotherapy is a promising first-line therapy for patients with advanced non-squamous non-small cell lung cancer (NSCLC). The cost-effectiveness of combinations with different ICIs is yet to be compared. Methods: We utilized Bayesian network meta-analyses for the comparisons of overall survival, progression-free survival, and incidence of adverse events of the included treatments in the total population and subgroups with different programmed death-ligand 1 tumor proportional scores (TPS). The cost-effectiveness of the treatments from the perspectives of the US and Chinese healthcare systems was assessed using Markov models. Results: Three combinations, including pembrolizumab + chemotherapy (PembroC), nivolumab + ipilimumab + chemotherapy (NivoIpiC), and atezolizumab + chemotherapy (AteC), were included in our study. In terms of efficacy, PembroC was most likely to be ranked first for extending progression-free survival (PFS) (93.16%) and overall survival (OS) (90.73%). Nevertheless, from the US perspective, NivoIpiC and PembroC showed incremental cost-effectiveness ratios (ICERs) of $68,963.1/quality-adjusted life-years (QALY) and $179,355.6/QALY, respectively, compared with AteC. The one-way sensitivity analysis revealed that the results were primarily sensitive to the hazard ratios for OS or the cost of immunotherapy agents. At a willingness-to-pay (WTP) threshold of $150,000/QALY, NivoIpiC had the highest probability of being cost-effective (63%). As for the Chinese perspective, NivoIpiC and PembroC had ICERs of $145,983.4/QALY and $195,863.3/QALY versus AteC, respectively. The results were primarily sensitive to the HRs for OS. At a WTP threshold of $38,017/QALY, AteC had the highest probability of cost-effectiveness (94%). Conclusion: Although PembroC has the optimal efficacy, NivoIpiC and AteC were the most favorable treatments in terms of cost-effectiveness for patients with advanced non-squamous NSCLC from the US and Chinese perspectives, respectively.

Cost-effectiveness analysis of osimertinib plus chemotherapy for patients with EGFR-mutated advanced non-small cell lung cancer.

INTRODUCTION: First-line osimertinib plus chemotherapy significantly prolonged progression-free survival of patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC) compared to osimertinib, according to the FLAURA2 trial. METHODS: We established a Markov model to compare the cost-effectiveness of osimertinib plus chemotherapy with that of osimertinib alone. Clinical data were obtained from the FLAURA and FLAURA2 trials, and additional data were extracted from online resources and publications. Sensitivity analyses were conducted to evaluate the robustness of the findings. We used A willingness-to-pay threshold of $150,000 per quality-adjusted life-years (QALYs) gained. The main outcomes were QALYs, overall costs, incremental cost-effectiveness ratio (ICER), incremental net monetary benefit, and incremental net health benefit. Subgroup analyses were conducted according to patients' mutation type and central nervous system (CNS) metastatic status. RESULTS: In a 20-year time horizon, the ICER of osimertinib plus chemotherapy versus osimertinib alone was $223,727.1 per QALY gained. The sensitivity analyses identified the cost of osimertinib and the hazard ratio for overall survival as the top 2 influential factors and a 1.9% probability of osimertinib plus chemotherapy to be cost-effective. The subgroup analyses revealed ICERs of $132,614.1, $224,449.8, $201,464.1, and $130,159.7 per QALY gained for L858R mutations, exon 19 deletions, CNS metastases, and no CNS metastases subgroups, respectively. CONCLUSIONS: From the perspective of the United States health care system, osimertinib plus chemotherapy is not cost-effective compared to osimertinib alone for treatment-naïve patients with EGFR-mutated advanced NSCLC, but more favorable cost-effectiveness occurs in patients with L858R mutations and patients without baseline CNS metastases.

Cost-effectiveness of tumor-treating fields plus standard therapy for advanced non-small cell lung cancer progressed after platinum-based therapy in the United States.

Background: Tumor treating fields (TTF) was first approved for treatment of glioblastoma. Recently, the LUNAR study demonstrated that TTF + standard therapy (ST) extended survival in patients with advanced non-small cell lung cancer (NSCLC). This primary objective of this study is to analyze the cost-effectiveness of this treatment from the United States healthcare payers' perspective. Methods: A 3-health-state Markov model was established to compare the cost-effectiveness of TTF + ST and that of ST alone. Clinical data were extracted from the LUNAR study, supplemented by additional cost and utility data obtained from publications or online sources. One-way sensitivity analysis, probabilistic sensitivity analysis, and scenario analysis were conducted. The willingness-to-pay (WTP) threshold per quality-adjusted life-years (QALYs) gained was set to $150,000. The main results include total costs, QALYs, incremental cost-effectiveness ratio (ICER) and incremental net monetary benefit (INMB). Subgroup analyses were conducted for two types of ST, including immune checkpoint inhibitor, and docetaxel. Results: During a 10-year time horizon, the costs of TTF + ST and ST alone were $431,207.0 and $128,125.9, and the QALYs were 1.809 and 1.124, respectively. The ICER of TTF + ST compared to ST was $442,732.7 per QALY, and the INMB was -$200,395.7 at the WTP threshold. The cost of TTF per month was the most influential factor in cost-effectiveness, and TTF + ST had a 0% probability of being cost-effective at the WTP threshold compared with ST alone. Conclusion: TTF + ST is not a cost-effective treatment for advanced NSCLC patients who progressed after platinum-based therapy from the perspective of the United States healthcare payers.

Micrometeorological monitoring reveals that canopy temperature is a reliable trait for the screening of heat tolerance in rice.

Micrometeorological monitoring is not just an effective method of determining the impact of heat stress on rice, but also a reliable way of understanding how to screen for heat tolerance in rice. The aim of this study was to use micrometeorological monitoring to determine varietal differences in rice plants grown under two weather scenarios-Long-term Heat Scenario (LHS) and Normal Weather Scenario (NWS)- so as to establish reliable methods for heat tolerance screening. Experiments were conducted with two heat susceptible varieties-Mianhui 101 and IR64-and two heat tolerant varieties, Quanliangyou 681 and SDWG005. We used staggered sowing method to ensure that all varieties flower at the same time. Our results showed that heat tolerant varieties maintained lower canopy temperature compared to heat susceptible varieties, not just during the crucial flowering period of 10 am to 12 pm, but throughout the entire day and night. The higher stomatal conductance rate observed in heat tolerant varieties possibly decreased their canopy temperatures through the process of evaporative cooling during transpiration. Conversely, we found that panicle temperature cannot be used to screen for heat tolerance at night, as we observed no significant difference in the panicle temperature of heat tolerant and heat susceptible varieties at night. However, we also reported that higher panicle temperature in heat susceptible varieties decreased spikelet fertility rate, while low panicle temperature in heat tolerant varieties increased spikelet fertility rate. In conclusion, the results of this study showed that canopy temperature is probably the most reliable trait to screen for heat tolerance in rice.

The scheme, and regulative mechanism of pyroptosis, ferroptosis, and necroptosis in radiation injury.

Radiotherapy (RT) stands as the primary treatment for tumors, but it inevitably causes damage to normal cells. Consequently, radiation injury is a crucial consideration for radiation oncologists during therapy planning. Cell death including apoptosis, autophagy, pyroptosis, ferroptosis, and necroptosis play significant roles in tumor treatment. While previous studies elucidated the induction of apoptosis and autophagy by ionizing radiation (IR), recent attention has shifted to pyroptosis, ferroptosis, and necroptosis, revealing their effects induced by IR. This review aims to summarize the strategies employed by IR, either alone or in combination therapy, to induce pyroptosis, ferroptosis, and necroptosis in radiation injury. Furthermore, we explore their effects and molecular pathways, shedding light on their roles in radiation injury. Finally, we summarize the regulative agents for these three types of cell death and their mechanisms. In summary, optimizing radiation dose, dose rate, and combined treatment plans to minimize radiation damage and enhance the killing effect of RT is a key focus.

Cancer stem cells: advances in knowledge and implications for cancer therapy.

Cancer stem cells (CSCs), a small subset of cells in tumors that are characterized by self-renewal and continuous proliferation, lead to tumorigenesis, metastasis, and maintain tumor heterogeneity. Cancer continues to be a significant global disease burden. In the past, surgery, radiotherapy, and chemotherapy were the main cancer treatments. The technology of cancer treatments continues to develop and advance, and the emergence of targeted therapy, and immunotherapy provides more options for patients to a certain extent. However, the limitations of efficacy and treatment resistance are still inevitable. Our review begins with a brief introduction of the historical discoveries, original hypotheses, and pathways that regulate CSCs, such as WNT/ß-Catenin, hedgehog, Notch, NF-κB, JAK/STAT, TGF-ß, PI3K/AKT, PPAR pathway, and their crosstalk. We focus on the role of CSCs in various therapeutic outcomes and resistance, including how the treatments affect the content of CSCs and the alteration of related molecules, CSCs-mediated therapeutic resistance, and the clinical value of targeting CSCs in patients with refractory, progressed or advanced tumors. In summary, CSCs affect therapeutic efficacy, and the treatment method of targeting CSCs is still difficult to determine. Clarifying regulatory mechanisms and targeting biomarkers of CSCs is currently the mainstream idea.

Cost-effectiveness of neoadjuvant pembrolizumab plus chemotherapy with adjuvant pembrolizumab for early-stage non-small cell lung cancer in the United States.

Introduction: Perioperative (neoadjuvant and adjuvant) pembrolizumab has shown favorable efficacy in patients with early-stage non-small cell lung cancer (NSCLC). This study aims to evaluate the cost-effectiveness of this treatment from the perspective of the United States healthcare payers. Methods: We established a Markov model to compare the cost-effectiveness of perioperative pembrolizumab with that of neoadjuvant chemotherapy in 21-day cycles, utilizing data from the phase 3 KEYNOTE-671 trial. Additional data were extracted from other publications or online sources. Sensitivity analyses were conducted to evaluate the robustness of the findings. A willingness-to-pay threshold of $150,000 per quality-adjusted life-years (QALYs) gained was established. The main outcomes of this study were the measurement of QALYs, overall costs, incremental cost-effectiveness ratio (ICER), and net monetary benefit (NMB). Results: During a 10-year time horizon, the total costs of perioperative pembrolizumab and the control treatment were $224,779.1 and $110,026.3, respectively. The QALYs were 4.19 and 2.97 for the two treatments, respectively, which led to an ICER of $94,222.29 per QALY gained. The NMB at the WTP threshold at $150,000 per QALY gained was $67,931.3. One-way sensitivity analysis identified the cost of pembrolizumab as the primary factor influencing cost-effectiveness. Probabilistic sensitivity analysis indicated a 97.7% probability of perioperative pembrolizumab being cost-effective at the WTP threshold. Conclusions: From the perspective of the United States healthcare payers, perioperative pembrolizumab is a cost-effective treatment for patients with early-stage NSCLC.

Simulation and Experimental Study of Laser Processing NdFeB Microarray Structure.

NdFeB materials are widely used in the manufacturing of micro-linear motor sliders due to their excellent permanent magnetic properties. However, there are many challenges in processing the slider with micro-structures on the surface, such as complicated steps and low efficiency. Laser processing is expected to solve these problems, but few studies have been reported. Therefore, simulation and experiment studies in this area are of great significance. In this study, a two-dimensional simulation model of laser-processed NdFeB material was established. Based on the overall effects of surface tension, recoil pressure, and gravity, the temperature field distribution and morphological characteristics with laser processing were analyzed. The flow evolution in the melt pool was discussed, and the mechanism of microstructure formation was revealed. In addition, the effect of laser scanning speed and average power on machining morphology was investigated. The results show that at an average power of 8 W and a scanning speed of 100 mm/s, the simulated ablation depth is 43 µm, which is consistent with the experimental results. During the machining process, the molten material accumulated on the inner wall and the outlet of the crater after sputtering and refluxing, forming a V-shaped pit. The ablation depth decreases with the increment of the scanning speed, while the depth and length of the melt pool, along with the height of the recast layer, increase with the average power.

Efficacy and safety of first-line immune checkpoint inhibitors combined with chemotherapy for extensive-stage small cell lung cancer: A network meta-analysis.

The efficacy and safety of first-line immune checkpoint inhibitors plus chemotherapy in the treatment of patients with extensive-stage small cell lung cancer (ES-SCLC) remains unevaluated, and there are no reports to directly compare the efficacy and safety among different immunotherapy (especially adebrelimab and surplulimab). Suitable phase III randomized controlled trials with two or more different arms were included. Independent reviewers screened and extracted relevant data and disagreements were resolved through consensus. Fixed-effect consistency models were used to calculate the overall survival (OS), progression-free survival (PFS), objective response rate, adverse events ≥ 3, and safety outcomes in the clinically relevant subgroups. In this network meta-analysis, six randomized controlled clinical trials (CAPSTONE-1, ASTRUM-005, CASPIAN, IMpower133, KEYNOTE-604, and an ipilimumab + chemotherapy trial) with totaling 3662 patients were involved. Compared to chemotherapy, immune checkpoint inhibitors plus chemotherapy present higher possibilities to bring about better OS and PFS. Serplulimab + chemotherapy significantly showed a better survival profit in comparison with ipilimumab + chemotherapy (0.67; 0.50-0.90). Compared with chemotherapy, adebrelimab + chemotherapy (0.72; 0,58-0.90), atezolizumab + chemotherapy (0.76; 0.60-0.96) durvalumab + chemotherapy (0.75; 0.62-0.91), and serplulimab + chemotherapy (0.63;0.49-0.82) all presented significantly better overall survival. In terms of progression-free survival, serplulimab + chemotherapy showed better efficacy in comparison with adebrelimab + chemotherapy (0.72; 0,53-0.97), atezolizumab + chemotherapy (0.62; 0.46-0.84), durvalumab + chemotherapy (0.60; 0.45-0.80). Compared with chemotherapy, adebrelimab + chemotherapy (0.67; 0.54-0.83) and serplulimab + chemotherapy (0.48; 0.48-0.86) all presented significantly better PFS. Immunotherapy plus chemotherapy had similar probabilities to cause adverse events of grade ≥ 3. In comparison with chemotherapy, immune checkpoint inhibitors plus chemotherapy were likely to be more suitable for the first-line treatment of ES-SCLC. According to our analysis, serplulimab plus chemotherapy and adebrelimab plus chemotherapy present higher possibilities to show better efficacy and safety, however, the level of evidence of this type of comparison is limited.

Corrigendum: Chronic Stress: Impacts on Tumor Microenvironment and Implications for Anti-Cancer Treatments.

[This corrects the article DOI: 10.3389/fcell.2021.777018.].

Chronic Stress: Impacts on Tumor Microenvironment and Implications for Anti-Cancer Treatments.

Chronic stress is common among cancer patients due to the psychological, operative, or pharmaceutical stressors at the time of diagnosis or during the treatment of cancers. The continuous activations of the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS), as results of chronic stress, have been demonstrated to take part in several cancer-promoting processes, such as tumorigenesis, progression, metastasis, and multi-drug resistance, by altering the tumor microenvironment (TME). Stressed TME is generally characterized by the increased proportion of cancer-promoting cells and cytokines, the reduction and malfunction of immune-supportive cells and cytokines, augmented angiogenesis, enhanced epithelial-mesenchymal transition, and damaged extracellular matrix. For the negative effects that these alterations can cause in terms of the efficacies of anti-cancer treatments and prognosis of patients, supplementary pharmacological or psychotherapeutic strategies targeting HPA, SNS, or psychological stress may be effective in improving the prognosis of cancer patients. Here, we review the characteristics and mechanisms of TME alterations under chronic stress, their influences on anti-cancer therapies, and accessory interventions and therapies for stressed cancer patients.

Anti-Angiogenic Therapy in the Treatment of Non-Small Cell Lung Cancer.

Angiogenesis plays an essential role in the development of most solid tumors by delivering nutrients and oxygen to the tumor. Therefore, anti-angiogenic therapy, particularly anti-VEGF and anti-VEGF receptor (VEGFR) therapy, has been a popular strategy to treat cancer. However, anti-angiogenic therapy does not significantly improve patients' outcomes when used alone because the cutdown of the vessels transforms tumor cells to a hypoxia-tolerant phenotype. While combining anti-angiogenic therapy with other therapies, including chemotherapy, radiotherapy, immunotherapy, and anti-epidermal growth factor receptor (EGFR) therapy, has a promising efficacy due to the vessel normalization effect induced by anti-angiogenic agents. Here, we review the characteristics of tumor angiogenesis, the mechanisms, clinical applications, and prospects of combining anti-angiogenic therapy with other therapies in the treatment of non-small cell lung cancer.