DLL3-guided therapies in small-cell lung cancer: from antibody-drug conjugate to precision immunotherapy and radioimmunotherapy.

DLL3 acts as an inhibitory ligand that downregulates Notch signaling and is upregulated by ASCL1, a transcription factor prevalent in the small-cell lung cancer (SCLC) subtype SCLC-A. Currently, the therapeutic strategies targeting DLL3 are varied, including antibody-drug conjugates (ADCs), bispecific T-cell engagers (BiTEs), and chimeric antigen receptor (CAR) T-cell therapies. Although rovalpituzumab tesirine (Rova-T) showed promise in a phase II study, it failed to produce favorable results in subsequent phase III trials, leading to the cessation of its development. Conversely, DLL3-targeted BiTEs have garnered significant clinical interest. Tarlatamab, for instance, demonstrated enhanced response rates and progression-free survival compared to the standard of care in a phase II trial; its biologics license application (BLA) is currently under US Food and Drug Administration (FDA) review. Numerous ongoing phase III studies aim to further evaluate tarlatamab's clinical efficacy, alongside the development of novel DLL3-targeted T-cell engagers, both bispecific and trispecific. CAR-T cell therapies targeting DLL3 have recently emerged and are undergoing various preclinical and early-phase clinical studies. Additionally, preclinical studies have shown promising efficacy for DLL3-targeted radiotherapy, which employs ß-particle-emitting therapeutic radioisotopes conjugated to DLL3-targeting antibodies. DLL3-targeted therapies hold substantial potential for SCLC management. Future clinical trials will be crucial for comparing treatment outcomes among various approaches and exploring combination therapies to improve patient survival outcomes.

Temporal patterns of organ dysfunction in COVID-19 patients hospitalized in the intensive care unit: A group-based multitrajectory modeling analysis.

BACKGROUND: The course of organ dysfunction (OD) in Corona Virus Disease 2019 (COVID-19) patients is unknown. Herein, we analyze the temporal patterns of OD in intensive care unit-admitted COVID-19 patients. METHODS: Sequential organ failure assessment scores were evaluated daily within 2 weeks of admission to determine the temporal trajectory of OD using group-based multitrajectory modeling (GBMTM). RESULTS: A total of 392 patients were enrolled with a 28-day mortality rate of 53.6%. GBMTM identified four distinct trajectories. Group 1 (mild OD, n = 64), with a median APACHE II score of 13 (IQR 9-21), had an early resolution of OD and a low mortality rate. Group 2 (moderate OD, n = 140), with a median APACHE II score of 18 (IQR 13-22), had a 28-day mortality rate of 30.0%. Group 3 (severe OD, n = 117), with a median APACHR II score of 20 (IQR 13-27), had a deterioration trend of respiratory dysfunction and a 28-day mortality rate of 69.2%. Group 4 (extremely severe OD, n = 71), with a median APACHE II score of 20 (IQR 17-27), had a significant and sustained OD affecting all organ systems and a 28-day mortality rate of 97.2%. CONCLUSIONS: Four distinct trajectories of OD were identified, and respiratory dysfunction trajectory could predict nonpulmonary OD trajectories and patient prognosis.

mTOR signaling promotes rapid m6A mRNA methylation to regulate NK-cell activation and effector functions.

Natural killer (NK) cells can be rapidly activated in response to cytokines during host defense against malignant cells or viral infection. However, it remains unclear what mechanisms precisely and rapidly regulate the expression of the numerous genes involved in activating NK cells. In this study, we discovered that NK-cell N6-methyladenosine (m6A) methylation levels were rapidly upregulated upon short-term NK-cell activation and were repressed in the tumor microenvironment. Deficiency of methyltransferase-like 3 (METTL3) or METTL14 moderately influenced NK-cell homeostasis, while double knockout of METTL3/14 significantly impacted NK-cell homeostasis, maturation, and antitumor immunity. This suggests a cooperative role of METTL3 and METTL14 in regulating NK-cell development and effector functions. Using methylated RNA immunoprecipitation sequencing (MeRIP-seq), we demonstrated that genes involved in NK-cell effector functions, such as Prf1 and Gzmb, were directly modified by m6A methylation. Furthermore, inhibiting mTOR complex 1 (mTORC1) activation prevented m6A methylation levels from increasing when NK cells were activated, and this could be restored by S-adenosylmethionine (SAM) supplementation. Collectively, we have unraveled crucial roles for rapid m6A mRNA methylation downstream of the mTORC1-SAM signal axis in regulating NK-cell activation and effector functions.

Preclinical Evaluation of Off-The-Shelf PD-L1+ Human Natural Killer Cells Secreting IL15 to Treat Non-Small Cell Lung Cancer.

We described previously a human natural killer (NK) cell population that upregulates PD-L1 expression upon recognizing and reacting to tumor cells or exposure to a combination of IL12, IL18 and IL15. Here, to investigate the safety and efficacy of tumor-reactive and cytokine-activated (TRACK) NK cells, human NK cells from umbilical cord blood were expanded, transduced with a retroviral vector encoding soluble (s) IL15, and further cytokine activated to induce PD-L1 expression. Our results show cryopreserved and thawed sIL15_TRACK NK cells had significantly improved cytotoxicity against non-small cell lung cancer (NSCLC) in vitro when compared to non-transduced (NT) NK cells, PD-L1+ NK cells lacking sIL15 expression (NT_TRACK NK), or NK cells expressing sIL15 without further cytokine activation (sIL15 NK cells). Intravenous injection of sIL15_TRACK NK cells into immunodeficient mice with NSCLC significantly slowed tumor growth and improved survival when compared to NT NK and sIL15 NK cells. The addition of the anti-PD-L1 atezolizumab further improved control of NSCLC growth by sIL15_TRACK NK cells in vivo. Moreover, a dose-dependent efficacy was assessed for sIL15_TRACK NK cells without observed toxicity. These experiments indicate that the administration of frozen, off-the-shelf allogeneic sIL15_TRACK NK cells is safe in preclinical models of human NSCLC and has potent antitumor activity without and with the administration of atezolizumab. A Phase I clinical trial modeled after this preclinical study using sIL15_TRACK NK cells alone or with atezolizumab for relapsed or refractory NSCLC is currently underway (NCT05334329).

Human anti-PSCA CAR macrophages possess potent antitumor activity against pancreatic cancer.

Due to the limitations of autologous chimeric antigen receptor (CAR)-T cells, alternative sources of cellular immunotherapy, including CAR macrophages, are emerging for solid tumors. Human induced pluripotent stem cells (iPSCs) offer an unlimited source for immune cell generation. Here, we develop human iPSC-derived CAR macrophages targeting prostate stem cell antigen (PSCA) (CAR-iMacs), which express membrane-bound interleukin (IL)-15 and truncated epidermal growth factor receptor (EGFR) for immune cell activation and a suicide switch, respectively. These allogeneic CAR-iMacs exhibit strong antitumor activity against human pancreatic solid tumors in vitro and in vivo, leading to reduced tumor burden and improved survival in a pancreatic cancer mouse model. CAR-iMacs appear safe and do not exhibit signs of cytokine release syndrome or other in vivo toxicities. We optimized the cryopreservation of CAR-iMac progenitors that remain functional upon thawing, providing an off-the-shelf, allogeneic cell product that can be developed into CAR-iMacs. Overall, our preclinical data strongly support the potential clinical translation of this human iPSC-derived platform for solid tumors, including pancreatic cancer.

RNA m5C modification upregulates E2F1 expression in a manner dependent on YBX1 phase separation and promotes tumor progression in ovarian cancer.

5-Methylcytosine (m5C) is a common RNA modification that modulates gene expression at the posttranscriptional level, but the crosstalk between m5C RNA modification and biomolecule condensation, as well as transcription factor-mediated transcriptional regulation, in ovarian cancer, is poorly understood. In this study, we revealed that the RNA methyltransferase NSUN2 facilitates mRNA m5C modification and forms a positive feedback regulatory loop with the transcription factor E2F1 in ovarian cancer. Specifically, NSUN2 promotes m5C modification of E2F1 mRNA and increases its stability, and E2F1 binds to the NSUN2 promoter, subsequently reciprocally activating NSUN2 transcription. The RNA binding protein YBX1 functions as the m5C reader and is involved in NSUN2-mediated E2F1 regulation. m5C modification promotes YBX1 phase separation, which upregulates E2F1 expression. In ovarian cancer, NSUN2 and YBX1 are amplified and upregulated, and higher expression of NSUN2 and YBX1 predicts a worse prognosis for ovarian cancer patients. Moreover, E2F1 transcriptionally regulates the expression of the oncogenes MYBL2 and RAD54L, driving ovarian cancer progression. Thus, our study delineates a NSUN2-E2F1-NSUN2 loop regulated by m5C modification in a manner dependent on YBX1 phase separation, and this previously unidentified pathway could be a promising target for ovarian cancer treatment.

Recent advances and remaining challenges in lung cancer therapy.

ABSTRACT: Lung cancer remains the most common cause of cancer death. Given the continued research into new drugs and combination therapies, outcomes in lung cancer have been improved, and clinical benefits have been expanded to a broader patient population. However, the overall cure and survival rates for lung cancer patients remain low, especially in metastatic cases. Among the available lung cancer treatment options, such as surgery, radiation therapy, chemotherapy, targeted therapies, and alternative therapies, immunotherapy has shown to be the most promising. The exponential progress in immuno-oncology research and recent advancements made in the field of immunotherapy will further increase the survival and quality of life for lung cancer patients. Substantial progress has been made in targeted therapies using tyrosine kinase inhibitors and monoclonal antibody immune checkpoint inhibitors with many US Food And Drug Administration (FDA)-approved drugs targeting the programmed cell death ligand-1 protein (e.g., durvalumab, atezolizumab), the programmed cell death-1 receptor (e.g., nivolumab, pembrolizumab), and cytotoxic T-lymphocyte-associated antigen 4 (e.g., tremelimumab, ipilimumab). Cytokines, cancer vaccines, adoptive T cell therapies, and Natural killer cell mono- and combinational therapies are rapidly being studied, yet to date, there are currently none that are FDA-approved for the treatment of lung cancer. In this review, we discuss the current lung cancer therapies with an emphasis on immunotherapy, including the challenges for future research and clinical applications.

Therapeutic application of human type 2 innate lymphoid cells via induction of granzyme B-mediated tumor cell death.

The therapeutic potential for human type 2 innate lymphoid cells (ILC2s) has been underexplored. Although not observed in mouse ILC2s, we found that human ILC2s secrete granzyme B (GZMB) and directly lyse tumor cells by inducing pyroptosis and/or apoptosis, which is governed by a DNAM-1-CD112/CD155 interaction that inactivates the negative regulator FOXO1. Over time, the high surface density expression of CD155 in acute myeloid leukemia cells impairs the expression of DNAM-1 and GZMB, thus allowing for immune evasion. We describe a reliable platform capable of up to 2,000-fold expansion of human ILC2s within 4 weeks, whose molecular and cellular ILC2 profiles were validated by single-cell RNA sequencing. In both leukemia and solid tumor models, exogenously administered expanded human ILC2s show significant antitumor effects in vivo. Collectively, we demonstrate previously unreported properties of human ILC2s and identify this innate immune cell subset as a member of the cytolytic immune effector cell family.

Development and Evaluation of a Nomogram for Predicting the Outcome of Immune Reconstitution Among HIV/AIDS Patients Receiving Antiretroviral Therapy in China.

This study aims to develop and evaluate a model to predict the immune reconstitution among HIV/AIDS patients after antiretroviral therapy (ART). A total of 502 HIV/AIDS patients are randomized to the training cohort and evaluation cohort. Least absolute shrinkage and selection operator (LASSO) regression and multivariate logistic regression analysis are performed to identify the indicators and establish the nomogram for predicting the immune reconstitution. Decision curve analysis (DCA) and clinical impact curve (CIC) are used to evaluate the clinical effectiveness of the nomogram. Predictive factors included white blood cells (WBC), baseline CD4+ T-cell counts (baseline CD4), ratio of effector regulatory T cells to resting regulatory T cells (eTreg/rTreg) and low-density lipoprotein cholesterol (LDL-C) and are incorporated into the nomogram. The area under the curve (AUC) is 0.812 (95% CI, 0.767∼0.851) and 0.794 (95%CI, 0.719∼0.857) in the training cohort and evaluation cohort, respectively. The calibration curve shows a high consistency between the predicted and actual observations. Moreover, DCA and CIC indicate that the nomogram has a superior net benefit in predicting poor immune reconstitution. A simple-to-use nomogram containing four routinely collected variables is developed and internally evaluated and can be used to predict the poor immune reconstitution in HIV/AIDS patients after ART.

Recent Advances of RNA m6A Modifications in Cancer Immunoediting and Immunotherapy.

Cancer immunotherapy, which modulates immune responses against tumors using immune-checkpoint inhibitors or adoptive cell transfer, has emerged as a novel and promising therapy for tumors. However, only a minority of patients demonstrate durable responses, while the majority of patients are resistant to immunotherapy. The immune system can paradoxically constrain and promote tumor development and progression. This process is referred to as cancer immunoediting. The mechanisms of resistance to immunotherapy seem to be that cancer cells undergo immunoediting to evade recognition and elimination by the immune system. RNA modifications, specifically N6-methyladenosine (m6A) methylation, have emerged as a key regulator of various post-transcriptional gene regulatory processes, such as RNA export, splicing, stability, and degradation, which play unappreciated roles in various physiological and pathological processes, including immune system development and cancer pathogenesis. Therefore, a deeper understanding of the mechanisms by which RNA modifications impact the cancer immunoediting process can provide insight into the mechanisms of resistance to immunotherapies and the strategies that can be used to overcome such resistance. In this chapter, we briefly introduce the background of cancer immunoediting and immunotherapy. We also review and discuss the roles and mechanisms of RNA m6A modifications in fine-tuning the innate and adaptive immune responses, as well as in regulating tumor escape from immunosurveillance. Finally, we summarize the current strategies targeting m6A regulators for cancer immunotherapy.

Infection Characteristics and Drug Susceptibility of Multidrug-Resistant Bacteria in Patients with Diabetic Foot Ulcers.

BACKGROUND: We aimed to analyze the infection characteristics of multidrug-resistant organisms (MDROs) and their resistance to antibiotics in patients with diabetic foot and provide guidance for the use of antibiotics in clinical practice. METHODS: The clinical data of 737 patients with diabetic foot who were hospitalized at our institution from February 2020 to January 2023 were retrospectively analyzed. Purulent secretions were collected from the patient's ulcers and bacterial culture, identification, and drug susceptibility tests were performed. The multidrug resistance (MDR) rate of different bacteria, composition ratio of MDROs, drug resistance characteristics of the main MDROs, distribution characteristics of multidrug-resistant gram-positive cocci and gram-negative bacilli in patients with different Wagner Grades, MDR in patients with different Wagner Grades, bacterial infection rate, and other indicators were analyzed. RESULTS: Pathogenic bacteria from wound secretions of 505 patients were cultured, and 509 pathogenic bacteria were obtained. Among the pathogenic bacteria, 225 strains were gram-positive cocci, of which 172 (76.44%) were MDROs, and 284 were gram-negative bacilli, of which 232 (81.69%) were MDROs. Among the 404 multidrug-resistant strains, gram-positive cocci and gram-negative bacilli accounted for 42.57% and 57.43%, respectively. The top five dominant MDROs were Staphylococcus aureus (18.56%), coagulase-negative Staphylococcus (10.89%), Escherichia coli (10.15%), Proteus mirabilis (8.17%), Proteus vulgaris (6.19%), and Pseudomonas aeruginosa (6.19%). Staphylococcus aureus and coagulase-negative Staphylococcus were more resistant to penicillin, oxacillin, erythromycin, azithromycin, and clarithromycin, with resistance rates of 50.0 - 95.0%. The resistance rates of E. coli to ampicillin, cefazolin, cefuroxime, ceftriaxone, and cefepime were > 75%. With an increase in Wagner Grade, the proportion of gram-negative bacilli among the pathogenic bacteria of MDROs increased significantly (p < 0.05), as did the infection rate of MDROs in patients with diabetic foot (χ2 = 14.045, p < 0.05). CONCLUSIONS: MDROs in patients with diabetic foot are mainly gram-negative bacilli, followed by gram-positive cocci. The drug resistance of various MDROs varies greatly. With the increase in Wagner Grade and MDR of diabetic foot patients, the infection rate of drug-resistant bacteria has increased significantly. Therefore, clinicians should use drugs rationally according to drug sensitivity results.

Acquired miR-142 deficit in leukemic stem cells suffices to drive chronic myeloid leukemia into blast crisis.

The mechanisms underlying the transformation of chronic myeloid leukemia (CML) from chronic phase (CP) to blast crisis (BC) are not fully elucidated. Here, we show lower levels of miR-142 in CD34+CD38- blasts from BC CML patients than in those from CP CML patients, suggesting that miR-142 deficit is implicated in BC evolution. Thus, we create miR-142 knockout CML (i.e., miR-142-/-BCR-ABL) mice, which develop BC and die sooner than miR-142 wt CML (i.e., miR-142+/+BCR-ABL) mice, which instead remain in CP CML. Leukemic stem cells (LSCs) from miR-142-/-BCR-ABL mice recapitulate the BC phenotype in congenic recipients, supporting LSC transformation by miR-142 deficit. State-transition and mutual information analyses of "bulk" and single cell RNA-seq data, metabolomic profiling and functional metabolic assays identify enhanced fatty acid ß-oxidation, oxidative phosphorylation and mitochondrial fusion in LSCs as key steps in miR-142-driven BC evolution. A synthetic CpG-miR-142 mimic oligodeoxynucleotide rescues the BC phenotype in miR-142-/-BCR-ABL mice and patient-derived xenografts.

Neuropsychiatric Adverse Events Following Antiretroviral Therapy in People Living with HIV: A Real-World Study of Dynamic Trends and Risk Factors in Hangzhou, China.

Purpose: Neuropsychiatric adverse events (NPAEs) occur frequently in people living with human immunodeficiency virus (PLWH) receiving antiretroviral therapy (ART). This study aimed to assess the dynamic trends and risk factors of NPAEs among PLWH in Hangzhou taking efavirenz (EFV)- or dolutegravir (DTG)- or elvitegravir (EVG)-based regimens. Patients and Methods: A total of 287 ART-naive PLWH were included in this study, EFV (400mg)- (n = 122), EFV (600mg)- (n = 37), DTG- (n = 73), EVG-based (n = 47) and other ART regimens (n = 8) as the initial ART regimen were administered for 12 months. All data were collected at five time points within a 12-month follow-up. The Pittsburgh Sleep Quality Index and Hospital Anxiety and Depression Scale were used to evaluate sleep disorders and anxiety and depression symptoms, respectively. The dynamic trends and potential risk factors of NPAEs were investigated using a generalized linear mixed model. Results: Mean age was 29.4 (SD: 7.5) years with 97.2% males. After 12 months of ART, the prevalence of sleep disorders and anxiety decreased significantly, although only a slight improvement was observed for depression. In addition, there was a significant positive correlation between sleep disorders, anxiety, and depression. The risk factors for NPAEs differed slightly depending on the choice of ART regimen, but the seven factors most commonly associated with NPAEs were age, sex, marital status, education level, smoking status, body mass index, and WHO clinical stage. Treatment-induced changes in CD4-positive T-cell count and virological suppression did not depend on the particular choice of ART regimen. Conclusion: The prevalence of sleep disorders and anxiety changed significantly over time on ART and the risks of these disorders were associated with seven common clinical and demographic factors.

Application of natural killer immunotherapy in blood cancers and solid tumors.

PURPOSE OF REVIEW: Natural killer (NK) cells are innate lymphoid cells characterized by their ability to attack aberrant and cancerous cells. In contrast to the activation of T-cells, NK cell activation is controlled by the interaction of NK cell receptors and their target cells in a manner independent of antigen organization. Due to NK cells' broad array of activation cues, they have gained great attention as a potential therapeutic agent in cancer immunotherapy. RECENT FINDINGS: Ex vivo activation, expansion, and genetic modifications, such as the addition of a chimeric antigen receptor (CAR), will allow the next generation of NK cells to enhance cytotoxicity, promote survival, and create "off-the-shelf" products. In addition to these that are poised to greatly enhance their clinical activity, the inherent lack of potential for causing graft-versus-host disease (GVHD) and cytokine release syndrome (CRS) suggest that CAR NK cells have the potential to be complementary to CAR-T cells as a component of therapeutic strategies for cancer. SUMMARY: In this review, we will provide a general understanding of NK cell biology, CAR-NK cell advantages over CAR-T cell therapy, barriers to making NK cell immunotherapy viable, and current NK cell clinical trials for hematological malignancies and solid tumors. The next generation of NK cells has potential to change the circumstances guiding present cancer immunotherapies.

Harnessing Natural Killer Cells for Lung Cancer Therapy.

Lung cancer is the leading cause of cancer-related death worldwide. Although natural killer (NK) cells are garnering interest as a potential anticancer therapy because they selectively recognize and eliminate cancer cells, their use in treating solid tumors, including lung cancer, has been limited due to impediments to their efficacy, such as their limited ability to reach tumor tissues, the reduced antitumor activity of tumor-infiltrating NK cells, and the suppressive tumor microenvironment (TME). This comprehensive review provides an in-depth analysis of the cross-talk between the lung cancer TME and NK cells. We highlight the various mechanisms used by the TME to modulate NK-cell phenotypes and limit infiltration, explore the role of the TME in limiting the antitumor activity of NK cells, and discuss the current challenges and obstacles that hinder the success of NK-cell-based immunotherapy for lung cancer. Potential opportunities and promising strategies to address these challenges have been implemented or are being developed to optimize NK-cell-based immunotherapy for lung cancer. Through critical evaluation of existing literature and emerging trends, this review provides a comprehensive outlook on the future of NK-cell-based immunotherapy for treating lung cancer.

Vincamine, from an antioxidant and a cerebral vasodilator to its anticancer potential.

Vincamine is a naturally occurring indole alkaloid showing antioxidant activity and has been used clinically for the prevention and treatment of cerebrovascular disorders and insufficiencies. It has been well documented that antioxidants may contribute to cancer treatment, and thus, vincamine has been investigated recently for its potential antitumor activity. Vincamine was found to show cancer cell cytotoxicity and to modulate several important proteins involved in tumor growth, including acetylcholinesterase (AChE), mitogen-activated protein kinase (MAPK), nuclear factor-κB (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), and T-box 3 (TBX3). Several bisindole alkaloids, including vinblastine and vincristine and their synthetic derivatives, vindesine, vinflunine, and vinorelbine, have been used as clinically effective cancer chemotherapeutic agents. In the present review, the discovery and development of vincamine as a useful therapeutic agent and its antioxidant and antitumor activity are summarized, with its antioxidant-related mechanisms of anticancer potential being described. Also, discussed herein are the design of the potential vincamine-based oncolytic agents, which could contribute to the discovery of further new agents for cancer treatment.

RBFOX2 recognizes N6-methyladenosine to suppress transcription and block myeloid leukaemia differentiation.

N6-methyladenosine (m6A) methylation can be deposited on chromatin-associated RNAs (caRNAs) by the RNA methyltransferase complex (MTC) to regulate chromatin state and transcription. However, the mechanism by which MTC is recruited to distinct genomic loci remains elusive. Here we identify RBFOX2, a well-studied RNA-binding protein, as a chromatin factor that preferentially recognizes m6A on caRNAs. RBFOX2 can recruit RBM15, an MTC component, to facilitate methylation of promoter-associated RNAs. RBM15 also physically interacts with YTHDC1 and recruits polycomb repressive complex 2 (PRC2) to the RBFOX2-bound loci for chromatin silencing and transcription suppression. Furthermore, we found that this RBFOX2/m6A/RBM15/YTHDC1/PRC2 axis plays a critical role in myeloid leukaemia. Downregulation of RBFOX2 notably inhibits survival/proliferation of acute myeloid leukaemia cells and promotes their myeloid differentiation. RBFOX2 is also required for self-renewal of leukaemia stem/initiation cells and acute myeloid leukaemia maintenance. Our study presents a pathway of m6A MTC recruitment and m6A deposition on caRNAs, resulting in locus-selective chromatin regulation, which has potential therapeutic implications in leukaemia.

Establishment of a Selective Liver Lobe Tumor-Bearing Mouse Model of Colorectal Cancer.

PURPOSE: Colorectal cancer is one of the most common causes of cancer-related death, and its main site of metastasis is the liver. The surgical method used for metastases of colorectal cancer in the liver varies according to the lobe affected, as does the prognosis. However, there is a lack of relevant basic research. Therefore, a good animal model is needed for basic studies of metastases from colorectal cancer to the different lobes of the liver. METHODS: A CT26 colon cancer cell line transfected with a virus expressing green fluorescent protein was inoculated into BALB/C mice via the spleen. Tumor formation in the liver lobes was observed under a fluorescence microscope according to which portal vein branch was ligated and according to clamping time. The differential formation of metastatic lesions in the different lobes was then compared with physical anatomy. Serum samples were used to detect the changes in liver function postoperatively. RESULTS: Ligation and resection of the spleen 1 min after injection of the CT26 cells and release of the vessel clamp 1 min after splenectomy created an ideal tumor-bearing mouse model with little effect on liver function. Selective clamping of each portal vein branch and splenic injection of a CT26 cell line successfully established a selective liver lobe tumor-bearing model of colorectal cancer with distinct characteristics. CONCLUSION: This model provides an opportunity for investigation of the mechanisms of metastasis of colorectal cancer to different lobes of the liver and may provide a basis for clinical treatment.