Postoperative recurrence remains a prevalent and lethal threat to survival in early-stage non-small cell lung cancer (NSCLC), affecting approximately 20

This study aimed to assess the genetic associations of metabolic syndrome (MetS) and its components with the onset and exacerbation of chronic obstructive pulmonary disease (COPD), including respiratory failure and pneumonia. Summary statistics were sourced from publicly available genome-wide association studies. Genetic instruments were selected at genome-wide significance and linkage disequilibrium clumped via PLINK software. Instrument strength was confirmed using F-statistics. Mendelian randomization (MR) analyses were performed using inverse-variance weighted, maximum likelihood, MR-Egger, and median-based approaches. Multivariable MR was performed to determine the independent effects of MetS and waist circumference (WC). Sensitivity analysis was performed to validate the robustness of the results. Statistical power was evaluated a priori using the mRnd. We controlled for multiple comparisons using the Benjamini-Hochberg false discovery rate procedure and reported the q-values. Using the inverse variance weighted method, MetS was associated with an increased risk of COPD onset (odds ratio [OR] = 1.27, 95% confidence interval [CI]: 1.14-1.40), respiratory insufficiency (OR = 1.66, 95% CI: 1.34-2.06), and pneumonia (OR = 1.13, 95% CI: 1.08-1.19). Among components, WC exhibited the strongest associations with COPD (OR = 1.69, 95% CI: 1.54-1.84), respiratory insufficiency (OR = 2.27, 95% CI: 1.89-2.72), and pneumonia (OR = 1.20, 95% CI: 1.16-1.25). Hypertension showed a nominal association with pneumonia (OR = 1.10, 95% CI: 1.00-1.20, P = .040, q = 0.103), which did not remain significant after false discovery rate correction. The other components showed no causal associations with COPD. Our study provides genetic evidence consistent with the causal contribution of MetS to COPD onset and exacerbation, with central adiposity (WC) emerging as the dominant driver. This finding supports closer respiratory risk assessment and prevention efforts among patients with MetS. Patients with comorbid COPD and MetS require personalized multidisciplinary strategies to prevent COPD exacerbation and slow progression.

Epidermal growth factor receptor (EGFR) mutations are major oncogenic drivers in non-small cell lung cancer (NSCLC), occurring in 30–50

BACKGROUND:Pulmonary enteric adenocarcinoma (PEAC) as a rare subtype of lung adenocarcinoma is sparsely reported. Currently, to achieve effective treatment and accurate prognosis prediction, the exploration of molecular markers is ongoing. METHODS:This study retrospectively enrolled 10 patients with PEAC confirmed by pathology at Zhejiang Cancer Hospital from April 2015 to July 2021. The investigation focused on their clinicopathological features and the tumor immune microenvironment. The expression of LAG-3, PD-L1, and MMR proteins was determined by immunohistochemistry in 7 patients with adequate tissue. Simultaneously, the levels and distribution of CD3, CD8A, CD45RO and PanCK in PEAC patients were measured by multiple immunohistochemical methods to explore and analyze the classification of TIME. RESULTS:A total of 10 patient pathologically diagnosed as PEAC, the mean age at diagnosis is 60.3 years, and 60% of them were male. The median follow-up for PFS subjects was 16.7 months (95%CI: 4.92-28.48 months). The median OS was 93.9 months (95% CI: 0-216.03 months). All the 7 patients in this study exhibited microsatellite stability (MSS), and PD-L1 expression was negative. Of the 7 patients, only one expressed LAG-3. The analysis of TIME in PEAC patients suggested 'cold tumors', meaning these patients may not benefit from immunotherapy. CONCLUSION:PEAC is a rare histological variant of LAUD that occurs predominantly in middle-aged and elderly males. Its morphological characteristics are similar to colorectal adenocarcinoma, and the NaspinA, TTF-1, CK7, CDX2 and CK20 are beneficial for diagnosis. In this study, PEAC patients showed low CD8+ T cell, CD45RO+ T cell and LAG-3 expression, and negative PD-L1 expression. And all patients were MMS.

Signal transducer and activator of (p-STAT) play a critical role in tumorigenesis, however, there is limited information on its prognostic value in non-small cell lung cancer (NSCLC). To address this question, 239 lung cancer and 71 normal lung tissue samples were obtained in this study. Immunohistochemistry was applied to detect STAT3/p-STAT 3 expression. Pearson's Chi-squared test and the Kaplanwith patients' clinical characteristics and survival. According to our results, STAT3/p-STAT3 was significantly upregulated in lung cancer tissue (p<0.001). correlated with age (p =0.046) and pathological types (p=0.037). In survival analysis, STAT3 positivity was 60 years (p =0.043) but failed to be an independent prognostic factor in multivariate analysis (p=0.083). biomarker in NSCLC.

Mounting evidence reveals that intratumoral microbiota, particularly Fusobacterium nucleatum (Fn), promote immunosuppression in the tumor microenvironment. We discovered that celastrol (CLT) displays concurrent cytotoxicity against triple-negative breast cancer (TNBC) cells and bactericidal effects against Fn. To exploit this unique dual-functionality, we developed a biomimetic system (CiTB) using hybrid membranes from engineered T cells and Fn to wrap CLT-loaded PLGA nanoparticles. This design utilizes overexpressed PD-1 on the T cell membrane and Fap2 proteins on the Fn membrane to target PD-L1 and Gal-GalNAc residues overexpressed on tumor cell surfaces, respectively. Importantly, this biomimetic system reprograms the tumor microenvironment through four synergistic effects: (1) directly clearing Fn to break bacteria-induced immunosuppression, (2) immune reactivation via PD-1 membrane mediated immune checkpoint blockade, (3) enhanced synergistic immunity characterized by NK cells and T cell infiltration, and (4) in-situ vaccination through combined bacterial component adjuvanticity and tumor antigen release. In Fn-colonized TNBC models, CiTB exhibited superior tumor accumulation and suppression as well as significant median survival length extension (from 23 to 44.5 days). CiTB also exhibited excellent biosafety without gut microbiome disruption. Thus, this study provides both a new nonantibiotic option for treating intratumor bacteria and a new biomimetic hybrid membrane technique for tumor targeting.

BackgroundCirculating tumor DNA (ctDNA) is evolving into a promising non-invasive approach for the detection of ALK rearrangement. This meta-analysis was designed to determine the diagnostic value of ctDNA for ALK rearrangement in lung cancer patients.MethodsWe performed a comprehensive publication search in Pubmed, Cochrane library, and Web of Science to identify the potentially relevant studies. Eligible studies were pooled to calculate the overall sensitivity, specificity, and diagnostic odds ratio (DOR). The area under the receiver operating-characteristic curve (AUC) was used to evaluate the overall diagnostic performance.ResultsThirteen eligible articles involving fourteen studies were identified in our meta-analysis, with a total of 1,138 participants. The pooled sensitivity, specificity, DOR, and AUC of ctDNA for ALK status detection were 0.61 (95% CI: 0.49, 0.72), 1.00 (95% CI: 0.98, 1.00), 188.19 (95% CI: 30.79, 1150.05) and 0.92, respectively. No publication bias was found among these studies (P = 0.42).ConclusionDetecting ALK rearrangement in ctDNA demonstrates adequate diagnostic accuracy and could serve as a highly specific test in lung cancer patients.

Background Clinical data is scarce in epidermal growth factor receptor (EGFR)-mutated lung squamous cell carcinoma (LUSC), and the resistance mechanisms to EGFR-tyrosine kinase inhibitor (TKI) is rarely studied. This study aimed to assess the efficacy of EGFR-TKI treatment in EGFR-mutated LUSC patients .Methods Data of a cohort of 99 LUSC patients who were treated with EGFR-TKI and were followed up to October 31, 2023.Results The objective response rate (ORR) of EGFR-mutated LUSC patients was higher than that of EGFR wild-type patients (44.4% vs 4.4%, p < 0.001). The progression-free survival (PFS) of EGFR-mutated LUSC patients receiving EGFR-TKI treatment was significantly longer than that of EGFR wild-type patients (6.4 months vs. 1.3 months; p < 0.001). Resistance mechanisms to EGFR-TKI in EGFR-mutated LUSC patients included secondary T790M mutations, 19 deletion-insertion mutations, MET amplification, histological transformation, and loss of EGFR mutations. The tumor immune microenvironment (TIME) of EGFR-mutated LUSC showed a downregulation of CD4 (p = 0.047) and CD8 (p = 0.14), and an upregulation of PD-L1 (p = 0.0021) after EGFR-TKI treatment failure.Conclusions EGFR-mutated LUSC patients receiving EGFR-TKIs treatment had higher ORR and longer PFS than EGFR wild-type LUSC patients.

BackgroundThe association between smoking status, cumulative smoking dose, and immunotherapy efficacy in non-small cell lung cancer (NSCLC) remains controversial. We sought to integrate the lifetime pack-years with smoking cessation status to identify optimal immunotherapy beneficiaries.MethodsA total of 1,192 immunotherapy-treated NSCLC patients treated between November 2015 and April 2024 were enrolled. Data on demographics, clinical characteristics, pathologic characteristics, treatments, and clinical outcomes were collected. The objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS) were compared across different smoking statuses (never, current, and former smokers) and cumulative smoking doses (never smokers, non-heavy smokers: <20 pack-years, and heavy smokers: ≥20 pack-years). Multivariate logistic regression and Cox proportional hazards models were used to analyze ORR and PFS, respectively.ResultsAmong the 1,192 patients, 377 were never smokers, 499 were current smokers, and 316 were former smokers. In terms of smoking status, former smokers exhibited the longest median PFS (17.0 months, P < 0.001), with the highest ORR (46.8%, P < 0.001) and DCR (86.7%, P = 0.008). Regarding cumulative smoking dose, the heavy smoker group demonstrated the longest median PFS (15.9 months, P = 0.001), with the highest ORR (46.6%, P < 0.001) and DCR (85.2%, P = 0.012). Notably, further multivariate analysis identified former heavy smokers as independent favorable predictors of ORR (OR = 1.93, 95% CI = 1.25–2.99, P = 0.003) and PFS (HR = 0.75, 95% CI = 0.57–0.99, P = 0.04) in advanced NSCLC patients receiving immunotherapy.ConclusionsThis real-world cohort analysis establishes a clinical stratification combining smoking cessation status with cumulative smoking dose, identifying former heavy smokers as optimal immunotherapy beneficiaries. These findings advocate integrated smoking history documentation and emphasize clinical prioritization of cessation interventions to enhance treatment efficacy in NSCLC.

Vaccines have proven effective in protecting populations against COVID-19, including the recombinant COVID-19 vaccine (Sf9 cells), the first approved recombinant protein vaccine in China. In this positive-controlled trial with 85 adult participants (Sf9 cells group: n = 44; CoronaVac group: n = 41), we evaluated the safety, immunogenicity, and protective effectiveness of a heterologous boost with the Sf9 cells vaccine in adults who had been vaccinated with the inactivated vaccine, and found a post-booster adverse events rate of 20.45% in the Sf9 cells group and 31.71% in the CoronaVac group (p = 0.279), within 28 days after booster injection. Neither group reported any severe adverse events. Following the Sf9 cells vaccine booster, the geometric mean titer (GMT) of binding antibodies to the receptor-binding domain of prototype SARS-CoV-2 on day 28 post-booster was significantly higher than that induced by the CoronaVac vaccine booster (100,683.37 vs. 9,451.69, p < 0.001). In the Sf9 cells group, GMTs of neutralizing antibodies against pseudo SARS-CoV-2 viruses (prototype and diverse variants of concern [VOCs]) increased by 22.23–75.93 folds from baseline to day 28 post-booster, while the CoronaVac group showed increases of only 3.29–10.70 folds. Similarly, neutralizing antibodies against live SARS-CoV-2 viruses (prototype and diverse VOCs) increased by 68.18–192.67 folds on day 14 post-booster compared with the baseline level, significantly greater than the CoronaVac group (19.67–37.67 folds). A more robust Th1 cellular response was observed with the Sf9 cells booster on day 14 post-booster (mean IFN-γ+ spot-forming cells per 2 × 105 peripheral blood mononuclear cells: 26.66 vs. 13.59). Protective effectiveness against symptomatic COVID-19 was approximately twice as high in the Sf9 cells group compared to the CoronaVac group (68.18% vs. 36.59%, p = 0.004). Our study findings support the high protective effectiveness of heterologous boosting with the recombinant COVID-19 vaccine (Sf9 cells) against symptomatic COVID-19 of diverse SARS-CoV-2 variants of concern, while causing no apparent safety concerns.

BackgroundAirway pressure release ventilation (APRV) has become increasingly popular for the management of acute respiratory distress syndrome (ARDS); however, its clinical impact remains a topic of debate. Furthermore, there is a gap between the guidelines and the actual clinical practices in mechanical ventilation management for ARDS. This survey aimed to explore the utilization of APRV and mechanical ventilation strategies for ARDS in Chinese intensive care unit (ICU) clinicians.MethodsA comprehensive 34-item survey was distributed online platforms amongst ICU clinicians across mainland China from June to August 2019.ResultsA total of 420 valid responses were collected, with 57.4% (241) originating from academic hospitals and 42.6% (179) from non-academic hospitals. Of the respondents, 98.6% (414) recognized the significance of low tidal volume ventilation for ARDS prognosis, 85.2% adhered to a tidal volume below 8 mL/kg predicted body weight, and most (46.4%) selected the initial positive end-expiratory pressure within the range of 5-10 cmH2O based on experience. Among the respondents, 62.1% (261) reported familiarity with APRV and 41.9% (176) had implemented APRV. Of those who had utilized APRV, 93.2% (164) believed in its effectiveness for ARDS patients and 69.3% (122) advocated for early application of APRV. Substantial variations were noted regarding APRV initiation settings and the preservation of spontaneous breathing during APRV. Academic hospitals exhibited higher usage rates of lung recruitment, neuromuscular blockade, prone ventilation, and acquaintance with and utilization of APRV compared to non-academic hospitals (all p values <= 0.001).ConclusionsOur findings highlight opportunities for improvement in mechanical ventilation management for ARDS, particularly in non-academic hospitals. Additionally, a significant proportion of clinicians demonstrated limited knowledge of APRV, and there was a lack of consensus on its application. Further training and larger-scale clinical trials are required to validate the efficacy and utilization of APRV in managing ARDS.

Lung cancer in never-smokers (LCINS) presents clinicopathological and molecular features distinct from that in smokers. Tumor microenvironment (TME) plays important roles in cancer progression and therapeutic response. To decipher the difference in TME between never-smoker and smoker lung cancers, we conduct single-cell RNA sequencing on 165,753 cells from 22 treatment-naive lung adenocarcinoma (LUAD) patients. We find that the dysfunction of alveolar cells induced by cigarette smoking contributes more to the aggressiveness of smoker LUADs, while the immunosuppressive microenvironment exerts more effects on never-smoker LUADs' aggressiveness. Moreover, the SPP1hi pro macrophage is identified to be another independent source of monocyte-derived macrophage. Importantly, higher expression of immune checkpoint CD47 and lower expression of major histocompatibility complex (MHC)-I in cancer cells of never-smoker LUADs imply that CD47 may be a better immunotherapy target for LCINS. Therefore, this study reveals the difference of tumorigenesis between never-smoker and smoker LUADs and provides a potential immunotherapy strategy for LCINS.

Background Early stage lung adenocarcinomas manifested as ground-glass nodules (GGNs) are increasingly being detected, but screening and diagnosis for GGN-featured lung adenocarcinomas in different risk populations reach no agreement. Objectives To analyze the clinical, pathological, imaging and genetic features of GGN-featured lung adenocarcinomas on high-resolution computed tomography (HRCT) in different risk groups. Methods Include patients with GGNs on HRCT surgically diagnosed as lung adenocarcinoma in the West China Hospital, Sichuan University from 2009 to 2021, and their clinical, pathological, imaging and gene sequencing data. Results According to Chinese Expert Consensus on Screening and Management of Lung Cancer, 1,800 patients with GGN-featured lung adenocarcinoma, 545 males (incl. 269 smokers) and 1,255 females (incl. 16 smokers), were divided into high-risk (509) and non-high-risk (1,291) groups. Among them, 1,095 were detected via physical examination. The mean age at diagnosis was 54.78 (23-84) and the mean time from detection to diagnosis was 9.59 months. There were more males than females in the high-risk group [288 (56.58%) vs 221 (43.42%)], just the opposite in the non-high-risk group [1,034 (80.09%) vs 257 (19.91%)] (both P < 0.001). No statistical difference was found in GGN detection way (P > 0.05). The frequency of invasive adenocarcinoma was higher in the high-risk group, while those of precursor lesions and minimally invasive adenocarcinoma were higher in the non-high-risk group (all P < 0.001). The preoperative follow-up time in the non-high-risk group was shorter (P < 0.05). A total of 711 gene mutations were observed in 473 patients with a ratio of non-high-risk to high-risk of 494:217. The incidence of EGFR mutation was not statistically significant (P = 0.824), while those of TP53 and KRAS mutations were higher in the high-risk group (P < 0.05). Conclusions GGN-featured lung adenocarcinoma is dominated by non-high-risk female patients. Shorter preoperative follow-up in the non-high-risk group and no statistical difference in GGN detection way suggests the existing screening criteria for high-risk population may not suit GGN-featured lung cancer. In addition, the incidences of KRAS and TP53 mutations are higher in the high-risk group.

Triple-negative breast cancer is often aggressive and resistant to various cancer therapies, especially corresponding targeted drugs. It is shown that targeted delivery of chemotherapeutic drugs to tumor sites could enhance treatment outcome against triple-negative breast cancer. In this study, we exploited the active tumor-targeting capability of macrophages by loading doxorubicin-carrying liposomes on their surfaces via biotin-avidin interactions. Compared with conventional liposomes, this macrophage-liposome (MA-Lip) system further increased doxorubicin accumulation in tumor sites, penetrated deeper into tumor tissue, and enhanced antitumor immune response. As a result, the MA-Lip system significantly lengthened the survival rate of 4T1 cell-bearing mice with low toxicity. Besides, the MA-Lip system used highly biocompatible and widely approved materials, which ensured its long-term safety. This study provides a system for triple-negative breast cancer treatment and offers another macrophage-based strategy for tumor delivery.

Red blood cell-derived extracellular vesicles (RBCEVs) are vesicles naturally produced by red blood cells and play multiple roles such as acting as cell-to-cell communication messengers in both normal physiological and diseased states. RBCEVs are highly promising delivery vehicles for therapeutic agents such as biomolecules and nucleic acids as they are easy to source, safe, and versatile. RBCEVs autonomously target the liver and pass the blood–brain barrier into the brain, which is highly valuable for the treatment of liver and brain diseases. RBCEVs can be modified by various functional units, including various functional molecules and nanoparticles, to improve their active targeting capabilities for tumors or other sites. Moreover, the RBCEV level is significantly shifted in many diseased states; hence, they can also serve as important biomarkers for disease diagnoses. It is clear that RBCEVs have considerable potential in multiple medical applications. In this review, we briefly introduce the biological roles of RBCEVs, presented interesting advances in RBCEV applications, and discuss several challenges that need to be addressed for their clinical translation.

Lung cancer is the most common malignancy and the leading cause of cancer death in China. Effective screening and early diagnosis can significantly improve the prognosis and reduce the risk of death in patients with lung cancer. Currently, low-dose computed tomography is the main screening method. Simultaneously, lung cancer-associated autoantibodies, artificial intelligence, and others have been gradually used in clinical practice. The development of respiratory interventional techniques such as endobronchial ultrasonography and virtual bronchoscopic navigation provide powerful tools for the accurate diagnosis of lung cancer at the early stage. In addition, new technologies such as liquid biopsy and exhaled breath analysis are expected to provide important tools for lung cancer screening and early diagnosis. However, each technique has its limitations, and optimization and combination may be the best choice. This paper reviews the status and challenges in the screening and early diagnosis of lung cancer to provide a reference for clinical doctors and researchers.

Heart failure (HF) is the end stage of various cardiovascular diseases, with high morbidity and mortality, and is associated with a poor prognosis. One of the primary causes of HF is aortic valve disease, manifested by progressive aortic valve stenosis (AVS), resulting in increased left ventricular load, ventricular hypertrophy, ultimately ventricular dysfunction, and HF. Early assessment of the degree of cardiomyopathy and timely intervention is expected to improve patients' cardiac function and delay or even avoid the occurrence of HF. The Wnt signaling pathway is mainly involved in regulating myocardial insufficiency after valve stenosis. Connexin 43 protein (Cx43) is an essential target of Wnt signaling pathway that forms gap junction (GJ) structures and is widely distributed in various organs and tissues, especially in the heart. The distribution and transformation of Cx43 among cardiac cells are crucial for the development of HF. To specifically label Cx43 in vivo, we established a new Cx43-BFP-GFP mouse model with two loxp sites on both sides of the tag BFP-polyA box, which can be removed by Cre recombination. This double-reporter line endowed us with a powerful genetic tool for determining the area, spatial distribution, and functional status of Cx43. It also indicated changes in electrical conduction between cells in a steady or diseased state.

BACKGROUND:We aimed to examine the different metastatic patterns and corresponding survival outcomes between all ages of young (aged <60 years) and elderly lung cancer patients.METHODS:Lung cancer patients from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015 were divided into a young and elderly group. The young group was subdivided into four consecutive subgroups. Baseline characteristics were analyzed by the Chi-square test. Survival differences were evaluated by Kaplan-Meier curves and Cox proportional hazards models.RESULTS:Of the total 200,362 lung cancer patients, 155,348 were elderly patients and 45,014 were young patients, including 3,461 aged <45 years, 5,697 aged 45-49 years, 13,645 aged 50-54 years, and 22,211 aged 55-59 years. Compared with elderly lung cancer patients, extrathoracic metastases were significantly more frequent in each younger group, irrespective of the site and number of extrathoracic metastatic organs. Regardless of metastasis patterns, young ages were independent prognostic factors of lung cancer-specific survival (LCSS) [<45 years: hazard ratio (HR): 0.70; 45-49 years: HR: 0.87; 50-54 years: HR: 0.90; 55-59 years: HR: 0.93, all P values were <0.001]. In each age subgroup, patients with multi-organ extrathoracic metastasis had the worst LCSS.CONCLUSIONS:Young lung cancer patients across all ages were at increased risk of extrathoracic metastasis, especially multi-organ patterns, but had a reduced risk of lung cancer-related death compared to elderly patients. Regular and meticulous monitoring of potential metastasized organs is required in young lung cancer patients throughout the follow-up period.

Worldwide, lung cancer is the most common malignancy and the leading cause of cancer-related death. After the era of chemotherapy, radiotherapy, and molecular-targeted therapy, the treatment of advanced lung cancer has entered a new era of immunotherapy, represented by immune checkpoint inhibitors (ICIs), including programmed cell death protein-1/programmed cell death protein ligand-1 (PD-1/PD-L1) inhibitors and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) inhibitors.[1] However, patients treated with ICIs may experience unexpected systemic toxicities, some fatal. Thus, managing immunotherapy-related toxicity has become increasingly significant in patients with lung cancer. Here, we review the latest developments on the clinical features and management of immunotherapy-related toxicity in patients with lung cancer in order to promote the standardization of immunotherapy for lung cancer. Clinical characteristics of immunotherapy-related toxicity The toxicities can occur in almost every tissues and organs throughout the body, including skin, endocrine system, liver, gastrointestinal tract, lung, cardiovascular system, musculoskeletal system, nervous system, eyes, hematologic system, etc. In the present review, we mainly focus on several common or fatal toxicities. Digestive toxicity The digestive system is one of the most common sites affected by ICIs; and digestive toxicities mainly manifest with hepatic toxicity (hepatitis) and gastrointestinal toxicity (diarrhea and colitis).[2,3] In clinical trials of PD-1/PD-L1 inhibitors, the incidences of any-grade hepatic and gastrointestinal toxicities range from 2–9% and 1–15%, respectively; and those of grade 3 or higher are <1–4% and <1–3%, respectively.[4–12] Notably, gastrointestinal toxicity is frequently observed in patients with CTLA-4 inhibitors other than PD-1/PD-L1 inhibitors; moreover, ICI combination may significantly increase the possibility. A meta-analysis of incidence of immunotherapy-related colitis in various solid cancers revealed that no significant differences in gastrointestinal toxicity incidences were observed among different cancers (eg, melanoma, non-small cell lung cancer [NSCLC], renal cell cancer [RCC]). Incidence of all-grade colitis with CTLA inhibitor monotherapy and PD-1/PD-L1 inhibitor monotherapy were 9.1% and 1.3%, respectively. Patients receiving ICI combination (ipilimumab plus nivolumab) had the highest rate of all-grade colitis (13.6%).[13] Endocrine toxicity The most common endocrine toxicity is thyroid dysfunction (hypothyroidism and hyperthyroidism). Other endocrine toxicities have also been reported, such as thyroiditis, hypophysitis, type one diabetes and primary adrenal insufficiency, but they are rare.[2,3] Specific regimens appear to be associated with specific endocrine toxicities. Thyroid dysfunction is seen more commonly with PD-1/PD-L1 inhibitors, whereas hypophysitis is seen more commonly with CTLA-4 inhibitors.[14] Following treatment of PD-1/PD-L1 inhibitors, 4–11% and 1–8% of patients with lung cancer experience any-grade hypothyroidism and hyperthyroidism, respectively; yet those of grade 3 or higher are rare (<1% for both).[4–11] Pulmonary toxicity Pulmonary toxicity is relatively common in lung cancer compared with other cancers; and it is the leading cause of immunotherapy-related deaths in lung cancer.[15] According to the preexisting clinical trials in patients with lung cancer treated with PD-1/PD-L1 inhibitors monotherapy, the incidence of any-grade pneumonitis ranges from 3% and 9%; and 1–3% of patients experience pneumonitis of grade 3 or higher.[4–12] Retrospective analyses suggest that old age (≥70 years), Asian ethnicity, former/current smoking status, squamous cell histological type, preexisting chronic lung disease (such as interstitial lung disease, chronic obstructive pulmonary disease [COPD]), combination therapy (PD-1/PD-L1 inhibitor plus CTLA-4 inhibitor, epidermal growth factor receptor-tyrosine kinase inhibitor plus PD-1/PD-L1 inhibitor) are associated with increased risk of pneumonitis.[15–18] On CT images, the radiologic findings include ground glass opacities (GGO), consolidations, bronchiectasis, interlobular septal thickening, and pleural effusions.[19] The radiologic features of pneumonitis are classified into four patterns: cryptogenic organizing pneumonia (COP), hypersensitivity pneumonitis (HP), acute interstitial pneumonia/acute respiratory distress syndrome (AIP/ARDS), and non-specific interstitial pneumonia (NSIP).[20] Cardiovascular toxicities Cardiovascular toxicity is rare in lung cancer, but it is highly lethal. Cardiovascular toxicities reported with ICIs in lung cancer include cardiomyopathy (mainly myocarditis), pericardial disease, arrhythmia, acute coronary syndrome, vascular disease and valve disease.[21] In a large-scale meta-analysis of fatal toxicities in cancers (including lung cancer), the mortality rate of myocarditis is up to 40%.[22] According to a recent real-world study, female, old age (≥75 years), and ICIs combination (ipilimumab plus nivolumab) may favor the occurrence of myocarditis.[23] Management of immunotherapy-related toxicity To date, several authoritative organizations have issued guidelines/consensus for immunotherapy; and the principles for management are comprehensive understanding, early recognition, timely detection, detailed assessment and effective management.[2,3,24–26] Before starting treatment, clinicians need to identify whether patients have underlying diseases or risk factors, including (1) pregnancy; (2) hepatitis B or C virus infection, human immunodeficiency virus (HIV) infection, or advanced age; (3) autoimmune diseases, hematopoietic stem cell transplantation or organ transplantation; and (4) poor general condition.[3] Pretreating laboratory tests such as complete blood count with differential, infectious disease screening panel, comprehensive metabolic panel; as well as imaging including CT scans of the chest, abdomen, and pelvis and echocardiography should be reviewed as baseline data.[3,12] Baseline data will be used as a reference for any abnormality occurring during immunotherapy. During and after the immunotherapy, any adverse events should be assessed for three potential causes: disease progression, an unforeseen event, or an immunotherapy-related toxicity.[18] The differential diagnosis can be based on clinical manifestations, laboratory tests, and endoscopy and imaging examination. Test results should always be compared with baseline to detect any changes over time. Once diagnosed with immunotherapy-related toxicity, it should be graded according to the Common Terminology Criteria for Adverse Events (CTCAE) standard, and treatment should be tailored to different grades.[2,12,19,20] (1) Grade one toxicity does not require hospitalization, and immunotherapy may continue. The use of corticosteroids or other immunosuppressants is usually not recommended. (2) Grade 2 toxicity also does not require hospitalization, but immunotherapy should be suspended temporarily. Patients can be treated with topical or systemic glucocorticoids. (3) Grade 3 toxicity requires hospitalization and suspension of immunotherapy. Systemic glucocorticoid treatment is usually suggested. (4) Grade 4 toxicity requires hospitalization, and shall be considered for admission to intensive care unit. ICI therapy is permanently discontinued. Apart from systemic glucocorticoid, intravenous immunoglobulin is also suggested. Notably, for patients with grade 3 or 4 toxicity, whose symptoms do not subside after 3 to 5 days of treatment, other immunosuppressive therapy (anti-tumor necrosis factor α antibody, alpha-4 beta-7 integrin inhibitors, mycophenolate-containing medicines, etc) may be considered under the guidance of a specialist. Prospect Immunotherapy has provided a powerful and promising tool in the treatment of advanced lung cancer. However, there are still some issues to be explored. First, how to identify risk factors for developing specific immunotherapy-related toxicity after treatment with ICIs, which would contribute to the identification of susceptible population and the early diagnosis of toxicity. Second, more attention should be paid to the incidence and features of immune-related toxicities in the extension of immunotherapy (such as combination of ICIs and tyrosine kinase inhibitors). Third, more studies are needed to explore the characteristics of immune-related toxicities in the Chinese population, as most of the current clinical trials have been conducted in Europe and the United States. In summary, we need to develop a more reasonable whole-course management program for the lung cancer patients receiving immunotherapy. Funding This work was supported by the National Natural Science Foundation of China (No. 81871890) to Wei-Min Li. Conflicts of interest None.