In recent years, the progression of stem cell therapies has shown great promise in advancing the nascent field of regenerative medicine. Considering the non-regenerative nature of the mature central nervous system, the concept that "blank" cells could be reprogrammed and functionally integrated into host neural networks remained intriguing. Previous work has also demonstrated the ability of such cells to stimulate intrinsic growth programs in post-mitotic cells, such as neurons. While embryonic stem cells demonstrated great potential in treating central nervous system pathologies, ethical and technical concerns remained. These barriers, along with the clear necessity for this type of treatment, ultimately prompted the advent of induced pluripotent stem cells. The advantage of pluripotent cells in central nervous system regeneration is multifaceted, permitting differentiation into neural stem cells, neural progenitor cells, glia, and various neuronal subpopulations. The precise spatiotemporal application of extrinsic growth factors in vitro, in addition to microenvironmental signaling in vivo, influences the efficiency of this directed differentiation. While the pluri- or multipotency of these cells is appealing, it also poses the risk of unregulated differentiation and teratoma formation. Cells of the neuroectodermal lineage, such as neuronal subpopulations and glia, have been explored with varying degrees of success. Although the risk of cancer or teratoma formation is greatly reduced, each subpopulation varies in effectiveness and is influenced by a myriad of factors, such as the timing of the transplant, pathology type, and the ratio of accompanying progenitor cells. Furthermore, successful transplantation requires innovative approaches to develop delivery vectors that can mitigate cell death and support integration. Lastly, host immune responses to allogeneic grafts must be thoroughly characterized and further developed to reduce the need for immunosuppression. Translation to a clinical setting will involve careful consideration when assessing both physiologic and functional outcomes. This review will highlight both successes and challenges faced when using human induced pluripotent stem cell-derived cell transplantation therapies to promote endogenous regeneration.

Epithelial ovarian cancer (EOC) progression is determined by numerous intracellular interactions and the interplay between malignant cells, normal cells, and the tumor acellular microenvironment, formed largely by the extracellular matrix (ECM). The structure and biochemical functioning of various ECM components, along with the activity of agents that regulate ECM remodeling, impact the disease's expansion (adhesion, proliferation, invasion), spread, and response to therapy. It is important to note that the involvement of ECM components and their regulators in the progression of EOC is bidirectional and distinctly depends on a particular tissue context. In certain situations, certain components of the ECM enhance the activity of cancer cells, but in other scenarios, they suppress it. In this review, we summarize the newest knowledge regarding diverse aspects of ECM engagement in EOC pathophysiology and chemotherapy. Moreover, we delineate conditions that exacerbate the pro-cancerous properties of ECM, including diabetes-associated glycation, aging, and cellular senescence. We also explore methods to therapeutically alter the properties of the ECM, which could be beneficial in ovarian cancer prevention and treatment.

Early clues to tumors and their microenvironments come from embryonic development. Here we review the literature and consider whether the embryonic brain and its pathologies can serve as a better model. Among embryonic organs, the brain is the most heterogenous and complex, with multiple lineages leading to wide spectrum of cell states and types. Its dysregulation promotes neurodevelopmental brain pathologies and pediatric tumors. Embryonic brain pathologies point to the crucial importance of spatial heterogeneity over time, akin to the tumor microenvironment. Tumors dedifferentiate through genetic mutations and epigenetic modulations; embryonic brains differentiate through epigenetic modulations. Our innovative review proposes learning developmental brain pathologies to target tumor evolution-and vice versa. We describe ways through which tumor pharmacology can learn from embryonic brains and their pathologies, and how learning tumor, and its microenvironment, can benefit targeting neurodevelopmental pathologies. Examples include pediatric low-grade versus high-grade brain tumors as in rhabdomyosarcomas and gliomas.

A protective effect of childhood vaccinations on leukemia risk, particularly acute lymphoblastic leukemia (ALL), has been hypothesized, though findings are inconsistent. We used a nationwide cohort of Danish children born 1997-2018 (n = 1,360,230), to examine associations between childhood vaccinations and leukemia (<20 years) using registry data (follow-up: December 31, 2018). Cox proportional hazard models with age as the underlying time estimated hazard ratios (HRs) for leukemia (any, ALL, acute myeloid [AML], and other), comparing vaccinated with unvaccinated children. We also accessed the effect of each additional vaccine dose. During 14,536,819 person-years, 771 children were diagnosed with leukemia (74% ALL, 16% AML, and 10% other). Any vaccination was associated with an increased HR for ALL (HR: 2.76; 95% CI: 0.66-11.58), compared to unvaccinated children, with a change in HR of 1.01 (95% CI: 0.96-1.05) per dose. The corresponding HRs for any leukemia, AML, and other leukemia were 1.04 (95% CI: 0.50-2.17), 0.67 (95% CI: 0.18-2.59) and 0.29 (95% CI: 0.09-0.99), with a change in HR of 0.97 (95% CI: 0.94-1.02), 0.92 (95% CI: 0.84-1.00, p = .062) and 0.88 (95% CI: 0.78-1.00, p = .044) per dose. No significant associations were found for vaccination types, except for the pneumococcal vaccine which was associated with a decreased risk of other leukemia (HR: 0.32; 95% CI: 0.14-0.74). In six-months lag analyses, no significant associations were observed, and decreased risks were attenuated. The results provide no strong evidence that childhood vaccinations reduce leukemia risk. The limited number of unvaccinated cases and wide confidence intervals suggest cautious interpretation of some findings.

The combination of oncolytic viruses (OVs) with other immunotherapies, such as immunostimulatory therapies, is a current research hotspot; however, optimizing their therapeutic potential remains to be fully explored. Here, we designed a novel oncolytic herpes simplex virus 2 expressing Fms-like tyrosine kinase 3 ligand (OH2-FLT3L), which induces an antitumor cytotoxic T cell immune response by activating dendritic cells (DCs). We found that OH2-FLT3L specifically infects tumor cells, induces immunogenic cell death (ICD), and releases a large number of tumor-specific antigens, which bound to danger signals and facilitated antigenic cross-presentation by DCs, significantly enhancing T cell activation and function. Experimental results showed that OH2-FLT3L significantly increased the proportion of activated DCs, enhanced the antitumor immune response, and effectively converted "cold" tumors into "hot" tumors. In addition, when combined with anti-PD-1 antibody, OH2-FLT3L further enhanced therapeutic efficacy. In conclusion, OH2-FLT3L, as a novel oncolytic virus, demonstrates the potential to enhance antitumor immune responses through DC activation.

Centromere protein W (CENP-W) is essential for chromosome segregation and mitotic assembly and has been recognized as a prognostic marker in several cancers. However, its significance in clear-cell renal cell carcinoma (ccRCC) remains underexplored. To investigate this, we analyzed transcriptomic data from the National Center for Biotechnology Information (NCBI) and The Cancer Genome Atlas (TCGA) to evaluate CENP-W expression and its associations with clinical outcomes, prognosis, and immune-related markers. Kaplan-Meier survival analysis indicated that elevated CENP-W levels are significantly associated with poorer overall survival in ccRCC patients. Further meta- and multivariate analyses confirmed CENP-W as an independent negative prognostic factor. Gene Set Enrichment Analysis (GSEA) revealed the involvement of CENP-W in immune-related pathways, notably PI3K-Akt and Wnt signaling. Pearson correlation analysis revealed strong associations between CENP-W expression and immune cell infiltration, cancer-associated fibroblasts (CAFs), CTLA4, and PDCD1. qRT-PCR assays confirmed elevated CENP-W levels in ccRCC samples. Additionally, GSEA and GO enrichment highlighted a relationship between CENP-W and lipid metabolism, with reduced CENP-W expression leading to a significant decrease in lipid droplet accumulation. This study identifies CENP-W as a potential biomarker and prognostic indicator in ccRCC, offering insights into personalized therapeutic strategies integrating tumor immunity to enhance the efficacy of immunotherapy.

Head and neck cancer (HNC) is the sixth most prevalent cancer worldwide with a poor prognosis when diagnosed at advanced clinical stages. The main risk factors are tobacco consumption and alcohol abuse. However, the incidence of oropharyngeal cancer (OPC) is increasing due to human papillomavirus (HPV) infection. Current diagnostic techniques for both HPV-positive and HPV-negative HNC often involve invasive, costly, and time intensive procedures. Alternatively, liquid biopsies have emerged as a minimally invasive technique which may lessen the burden of cancer diagnoses on both patients and healthcare resources. This technique analyzes biological components released by tumors into the bloodstream, such as circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), exosomes, tumor proteins, and methylation changes, allowing for specific cancer detection and surveillance. This article reviewed the status and clinical applications of ctDNA and CTCs in the diagnosis and treatment of HPV-positive HNC. In addition, a systematic review following PRISMA 2020 Checklist (PROSPERO ID: 560498) was conducted to investigate whether liquid biopsies could be leveraged to assess the role of the immune system on treatment outcomes and the overall survival of HNC patients. Two public databases (Medline and Embase) were searched using relevant MeSH (Medical Subject Headings) terms and keywords. After multiple rounds of screening, eight studies published between 2017 and 2024 involving 814 cancer patients from three different countries were retained for data extraction. The data demonstrated that the immune microenvironment of HNC patients could be characterized via liquid biopsy, however, future validation is required. Furthermore, through the detection of HPV ctDNA, liquid biopsy technology has shown promise in diagnostics, as a predictor of patient prognoses and treatment responses, and as a tool to monitor disease progression in HPV-positive HNC.

Resistance to immune checkpoint inhibitors remains a significant challenge in the treatment of cancer. Emerging evidence suggests that metabolic reprogramming plays a crucial role in tumor metabolism and progression. Our study strived to investigate the role and underlying mechanisms of the glutamate transporter SLC1A6 in resistance to immunotherapy of cancer.

Single-cell RNA sequencing was performed on bladder cancer patients receiving neoadjuvant immunotherapy to identify the expression of SLC1A6 in treatment-resistant cases. The clinical prognostic value of SLC1A6 in cancer was validated using publicly available lung cancer single-cell datasets, as well as transcriptomic data from both bladder and lung cancer cohorts. Flow cytometry was employed to assess the impact of SLC1A6 knockdown on the effector function of CD8⁺ T cell. In vivo tumor models were used to evaluate the role of SLC1A6 in immunotherapy resistance, with immunofluorescence staining performed to examine GZMB⁺ CD8⁺ T cell infiltration.

SLC1A6 was highly expressed in bladder cancer patients resistant to neoadjuvant immunotherapy, and its expression was associated with disease progression, poor prognosis, and low immune infiltration. Knockdown of SLC1A6 in tumor cells enhanced CD8⁺ T cell effector function. SLC1A6 knockdown also improved the efficacy of immunotherapy and increased the infiltration of GZMB⁺ CD8⁺ T cells within the tumor microenvironment.

SLC1A6 plays a critical role in resistance to immunotherapy in cancer. Targeting SLC1A6 may provide a promising therapeutic strategy for improving responses to neoadjuvant immunotherapy and advancing combination treatment approaches.

Background/Objectives: The early detection of high levels of CBC-derived inflammatory biomarkers and cellular lines, as well as their variations across different histological subtypes of lung cancer, may aid in the early identification of high-risk lung cancer patients and further guide their clinical approach. Methods: A retrospective descriptive study was conducted and included 202 patients diagnosed with lung carcinoma at the Clinical County Hospital Mureș. The main analyzed parameters were the histological subtype and the stage of the tumor at diagnosis, white blood cell counts, and platelet counts, as well as nine CBC-derived inflammatory indexes like neutrophil-to-lymphocyte ratio (NLR), derived neutrophil-to-lymphocyte ratio (d-NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), eosinophil-to-neutrophil ratio (ENR), eosinophil-to-monocyte ratio (EMR), systemic inflammatory index (SII), systemic inflammatory response index (SIRI), and aggregate index of systemic inflammation (AISI). The statistical analysis was performed using the MedCalc software, version 23.0.2. Logarithmic ANOVA was used to compare groups. Normality was tested using the Shapiro-Wilk test. The Chi-square test compared categorical variables, while the independent Mann-Whitney test was used for continuous variables. Results: The inflammatory response increased as disease severity progressed, with NSCLC-NOS being the histological subtype with the most numerous patients outside the normal ranges. Eosinophil count differed significantly across the histologic subtypes of NSCLC, with adenocarcinoma and adenosquamous patients exhibiting the highest values. In adenocarcinoma patients, we observed that NLR and MLR levels increased progressively as the tumor stage advanced. Based on severity, differences were observed across the histological subtypes of lung cancer in stage III patients for ENR, EMR, AISI, eosinophil count, and platelet count, as well as in stage IV patients for AISI, SIRI, and SII. Disease severity impacts the associated inflammatory response in all histologic subtypes of lung cancer to varying degrees. Conclusions: Histological subtype might have a decisive role in shaping the systemic inflammatory profile of lung cancer patients. CBC-derived indices serve as accessible, cost-effective biomarkers for early risk assessment, aiding in the prognosis evaluation and monitoring of therapeutic response. Future studies are needed to further evaluate the histology-specific inflammatory profiles as adjunctive tools in precision oncology.

Necroptosis has been shown to play an important role in various pathologies, including pancreatic cancer (PDAC). However, its role in the progression of oral cancer (OSCC) remains unclear.

To determine the expression of key necroptosis pathway markers in an OSCC mouse model and evaluate the therapeutic effect of a necroptosis inhibitor on the progression of OSCC.

4-NQO-induced OSCC in mice resembles very closely to human OSCC. The expression of RIPK-1, RIPK-3, MLKL and their respective phosphorylation was increased in OSCC tissues of cancer-bearing mice. In the analysis of the necroptosis pathway in human OSCC with the TCGA database, we found similar overexpression of RIPK-1 in human cancer, which correlated with the severity of cancer in terms of different cancer grades and stages. Pharmacological blockade of necroptosis with necrostatin-1 (NEC-1) reduced the progression and development of OSCC, characterized by reduced number and severity of tumour lesions, improved histology with reduced hyperplasia, dysplasia and invasive carcinoma. Immune profiling of blood, spleen and tumour tissues demonstrated suppressed expression of MDSCs (CD11b+Gr-1+) and M2-macrophages (CD11b+F4/80+CD206+), while M1-macrophages (CD11b+F4/80+MHCII+) were elevated in the treatment group. The ratio of M2/M1 was reduced in the treated group, suggesting the promotion of anti-tumour immune response. Expression of Arg-1, YM1/2, IL-10 and TGF-β was reduced in tumour tissues in the treated group.

In summary, blocking the necroptosis pathway alters the tumour microenvironment (TME) and inhibits the progression of OSCC. Targeting necroptosis could be an effective therapy for treating OSCC in a clinical setup.

Imaging reporters have been widely employed in cancer research to monitor real-time tumor burden and metastatic spread. These tools offer a valuable approach for non-invasive imaging of tumor dynamics over time. With the established understanding that tumor immunology plays a critical role in cancer progression, it is essential to ensure that the chosen imaging reporters used to study tumor-immune interactions do not inadvertently elicit an immune response. This study aimed to investigate the immune response to bioluminescence reporters used for in vivo tracking of tumor cells in immunocompetent murine models.

The in vitro and in vivo growth effects of two stably expressed bioluminescence reporter genes, a red-shifted firefly luciferase and a click beetle green luciferase, were evaluated in four different cancer cell lines. Differences in parental and reporter-expressing cancer cell immune cell composition, activation, and secreted cytokine levels were evaluated using flow cytometry, cytokine arrays and ELISAs.

The data revealed no significant differences in in vitro cell proliferation between parental and reporter cancer cell lines. In vivo subcutaneous tumor growth was not observed in tumor cells stably expressing the red-shifted firefly luciferase. Cells labeled with click beetle green luciferase demonstrated no significant differences in in vivo subcutaneous tumor growth compared to parental cells. Tumor cells expressing red-shifted firefly luciferase induced an increase in activated and cytotoxic T cells compared to parental and click beetle green luciferase, suggesting enhanced immunogenicity. Furthermore, the tumor-immune composition and cytokine production were similar between parental and click beetle green luciferase-labeled tumor cells.

These findings demonstrate that the stable expression of click beetle green luciferase in cancer cells, in contrast to red-shifted firefly luciferase, has minimal immunogenicity and does not alter tumor development in immunocompetent mice. We report detailed characterization studies of bioluminescence reporter cells, providing essential considerations for their use in investigating tumor-immune interactions in syngeneic murine tumor models.

Breast cancer (BC) is the most prevalent form of cancer in women worldwide and the main cause of cancer-related fatalities in females. BC can be classified into various types based on where cancer has begun to grow or spread, specific characteristics that influence how cancer behaves, and treatment choices. BC is multifaceted, and due to its diverse nature, the mechanisms involved are complex and have not yet been understood. Overexpression and expression of various factors involved in the functioning of mechanisms lead to abnormal changes, providing an environment supporting cancer cell growth. Understanding BC risk factors and early diagnosis through screening techniques like mammography and diagnostic techniques such as imaging and biopsies has advanced significantly. A wide range of treatment options, including surgery, radiation, chemotherapy, targeted treatments, and hormonal therapies, are now available. Daily advancements are being made in the clinical treatment of BC. Still, BC drug resistance cases remain highly prevalent and are currently one of the biggest problems faced by medical science. To increase response rates and possibly lengthen survival, there is a critical requirement for novel medicines with minimal sensitivity to overcome drug resistance. This review classifies different mechanisms that are involved in the development of BC and workable pharmacological targets and explains how they relate to the development of BC drug resistance. By concentrating on the mechanisms covered in this review, we can have a deep understanding of different mechanisms and learn innovative ways to develop novel therapeutics for the disease to combat medication resistance.

Understanding the causal relationships between immune cell populations and cancer development remains a critical challenge in tumor immunology.

We employed Mendelian Randomization analysis leveraging genome-wide association studies of 612 immune cell traits and 91 cancer types to systematically evaluate causal associations. Single-cell RNA sequencing and computational deconvolution analyses were performed to characterize myeloid cell subpopulations in melanoma samples.

Our analysis revealed significant relationships between specific immune cell subsets and cancer risk, particularly highlighting the role of CD33 + myeloid cells in melanoma pathogenesis. Single-cell RNA sequencing identified distinct CD33high myeloid subpopulations characterized by elevated expression of complement cascade components and chemokine signaling pathways. Through computational deconvolution of The Cancer Genome Atlas melanoma cohort, we demonstrated that elevated CD33high monocyte abundance correlates with increased immune dysfunction scores, reduced CD8 + T cell infiltration, and poor survival outcomes.

Here we delineate the multifaceted mechanisms through which CD33 + myeloid cell populations orchestrate perturbations in the tumor-immune microenvironmental landscape, manifesting in compromised immunosurveillance and enhanced tumor progression. Our findings illuminate novel therapeutic opportunities through targeted modulation of myeloid cell function, while providing a systematic framework for understanding the complex interplay between immune cell populations and oncogenic processes.

Small cell lung cancer (SCLC) remains a challenge prognostically. A clinically silent early stage and predilection for early metastasis leads to over half of patients presenting with metastatic disease at the time of diagnosis. Akin to many other cancers, once SCLC metastasizes, current therapies begin to lose their effectiveness. The future of SCLC rests in innovative treatments aimed at improving patient outcomes. Chemotherapy and radiation remain the backbone treatment for SCLC. Most patients diagnosed with SCLC begin treatment with combination chemotherapy consisting of a platinum analog and topoisomerase inhibitor with or without concurrent radiation. Disease progression or recurrence warrants new treatment approaches. New chemotherapy combinations and advances in radiation precision offer patients novel approaches using the same backbone of treatment used in many other cancers. The introduction of newer therapeutic approaches, such as immune checkpoint inhibitors, small molecule targeted therapies, bispecific antibodies, and antibody-drug conjugates offer a bright future for patients with SCLC who fail first-line therapy. This review will focus on advancing treatment paradigms for SCLC in the era of precision medicine. Such a study might be helpful for pulmonologists and oncologists to manage precisely patients with SCLC.

While the effects of cancer vaccines have been extensively studied in the therapeutic setting, research has been more limited in the areas of cancer prevention and interception. Although cancer prevention by vaccines has been possible for viral-mediated cancers, such as cervical cancers and hepatocellular carcinoma, preventing non-viral cancers by immunopreventive vaccines is challenging. Many tumors at late stages are less responsive to treatments, including immunotherapies and vaccines, in part due to an immunosuppressive microenvironment. Shifting the strategy to intervention at early stages of cancer development and progression and focusing on high-risk cohorts with defined molecular targets offers a pathway for improved vaccine efficacy. Current research on the role of immune mechanisms during tumor initiation and progression is rapidly evolving and recent emerging preclinical immunoprevention studies have shown that vaccines can induce host immune response and effectively control tumor onset and progression. In this review, we address important considerations and challenges regarding the development of cancer immunoprevention for non-viral cancers. We also discuss significant, innovative, and impactful preclinical and clinical immunoprevention studies in various cancers. This includes neoantigen discovery, the use and optimization of immunomodulating agents either alone or in combination with vaccines, and strategies for optimizing vaccines. We conclude by discussing prospects for immunoprevention research and potential opportunities to advance the field in the future.

The tumor microenvironment (TME) plays a crucial role in the occurrence and progression of gastric cancer. Yet, we still don't understand how immune and stromal components of TMEs are modulated. In this study, we applied the ESTIMATE algorithm to calculate the number of immune and stromal components in 410 STAD cases in the Cancer Genome Atlas (TCGA) database. COX regression analysis and protein-protein interaction (PPI) network construction were used to analyze differentially expressed genes (DEGs). Then, P-selectin (SELP) was identified as a predictor by cross-analysis of univariate COX and PPI. After verifying the clinical significance of SELP for study, we performed an immune infiltration analysis and identified 54 immunomodulators associated with SELP through public data. Immunomodulation associated with gastric cancer prognosis was then confirmed by LASSO regression, and the previous results were further validated with single-cell data. Finally, we verified that SELP can promote EMT on gastric cancer cells. In conclusion, we validated that SELP may affect the biological phenotype of gastric cancer with the immune microenvironment alteration of gastric cancer.

Azvudine and nirmatrelvir/ritonavir are recommended as priority treatments for SARS-CoV-2 infection in China, but their effectiveness and safety in patients with pre-existing chronic liver diseases remains unknown.

We conducted a multicenter retrospective cohort study of hospitalized SARS-CoV-2 infected patients with chronic liver diseases in ten hospitals of Henan Province. Azvudine recipients were 2:1 propensity score matched with nirmatrelvir/ritonavir recipients. Efficacy and safety were evaluated by Kaplan-Meier analysis, multivariable Cox regression model, subgroup analysis, as well as sensitivity analyses.

Among 37606 hospitalized patients infected with SARS-CoV-2, 1355 azvudine recipients and 373 nirmatrelvir/ritonavir recipients met the inclusion criteria. Patients with azvudine treatment showed comparable effectiveness to nirmatrelvir/ritonavir with regard to both all-cause death (P = 0.34) and composite disease progression (P = 0.32), even after adjusting for other covariates (all-cause death: HR: 0.80, 95%CI: 0.574-1.128; composite disease progression: HR: 1.31, 95%CI: 0.999-1.723). Notably, compared with nirmatrelvir/ritonavir, azvudine showed better effectiveness for patients with a comorbidity of primary malignant tumor in reducing all-cause death. Four sensitivity analyses further confirmed the robustness.

The effectiveness of azvudine may potentially comparable to nirmatrelvir/ritonavir in SARS-CoV-2 infected patients with pre-existing liver diseases with respect to all-cause death and composite disease progression, without serious safety concerns. Due to the existence of potential biases, further studies still need to evaluate the efficacy of these two drugs.

The trial was retrospectively registered at ClinicalTrials.gov (CT.gov identifier: NCT06349655).

Long non-coding RNAs (lncRNAs) have emerged as pivotal regulators of the dynamic interplay between cancer progression and immune responses. This review explored their influence on key processes of the cancer-immunity cycle, such as immune cell differentiation, antigen presentation, and tumor immunogenicity. By modulating tumor escape from the immune response, therapeutic resistance, and tumor-stroma interactions, lncRNAs actively shape the tumor microenvironment. Due to their growing knowledge in the area of immune suppression, directly intervening in the induction of regulatory T cells (Tregs), M2 macrophages, and regulating immune checkpoint pathways such as PD-L1, CTLA-4, and others, lncRNAs can be considered promising therapeutic targets. Advances in single-cell technologies and immunotherapy have significantly expanded our understanding of lncRNA-driven regulatory networks, paving the way for novel precision medicine approaches. Ultimately, we discussed how targeting lncRNAs could enhance cancer immunotherapy, offering new avenues for biomarker discovery and therapeutic intervention.

Endocrine-disrupting chemicals (EDCs) are natural or synthetic compounds that are ubiquitous in the environment and in daily-usage products and interfere with the normal function of the endocrine system leading to adverse health effects in humans. Exposure to these chemicals might elevate the risk of metabolic disorders, developmental and reproductive defects, and endocrine-related cancers. Prostate cancer is the most common hormone-dependent cancer in men, and the fifth leading cause of cancer-related mortality, partly owing to a lack of knowledge about the mechanisms that lead to aggressive castration-resistant forms. In addition to the dependence of early-stage prostate cancer on androgen actions, the prostate is a target of oestrogenic regulation. This hormone dependence, along with the fact that exogenous influences are major risk factors for prostate cancer, make the prostate a likely target of harmful actions from EDCs. Various sources of EDCs and their different modes of action might explain their role in prostate carcinogenesis.

The gut microbiota has been closely associated with the pathogenesis of colorectal cancer (CRC). However, precise identification of particular microorganisms promoting CRC carcinogenesis, and more importantly those blocking tumor development, has been challenging based on human gut microbiota profiling studies. With a well-established azoxymethane/dextran sodium sulfate induction murine CRC model, we found a subset of mice consistently failed to develop CRC. This genetically homogeneous but cancer-refractory population gave us a unique opportunity to reveal that the microbial compositions between mice with and without CRC formation are indeed distinct, indicating key different gut microbiota between those groups are responsible for the differential susceptibility of the animals to CRC development. Our analysis revealed that Ruminococcus flavefaciens (R.f) and Fibrobacter succinogenes (F.s) were significantly enriched in CRC-free mice, while the presence of Eubacterium dolichum (E.d) was dramatically reduced. The correlative evidence was further substantiated as important causal factors, with subsequent bacteria intragastric administration experiments demonstrating independent, protective roles of R.f and F.s and a correspondingly detrimental role of E.d in inflammation-induced CRC initiation. Notably, E.d strongly activates NF-κB and promotes the local accumulation of myeloid-derived suppressor cells and macrophages. Significant disturbance of gut immune homeostasis, therefore, might be a critical trigger leading to subsequent CRC development. These findings indicate a clear direction for precise and rational gut microbiota-mediated CRC prevention.IMPORTANCEThere is a complex ecosystem of different microbes residing within the gut, which is highly relevant to health and diseases. The causal linkage between specific gut microbes and the development of colorectal cancer has been established with a mouse model, pinpointing specific bacteria species either promoting or preventing colorectal cancer development. A key aspect of these gut residual bacteria in colorectal cancer development is through exaggerating or easing gut inflammation. Therefore, by taking probiotics composed of corresponding cancer-preventing bacteria from human microbiota, it can be an effective and economic way to reduce human colorectal cancer risks.

Tumor controls its immunity by educating its microenvironment, including regulating polarity of tumor associated macrophages. It is well documented that cancer cells release PKM2 to facilitate tumor progression. We report here that the extracellular PKM2 (EcPKM2) modulates tumor immunity by facilitating M2 macrophage polarization in tumors. EcPKM2 interacts with integrin αvβ3 on macrophage to activate integrin-FAK-PI3K signal axis. Activation of FAK-PI3K by EcPKM2 suppresses PTEN expression, which subsequently upregulates arginase1 (Arg1) expression and activity in macrophage to facilitate M2 polarity. Our studies uncover a novel and important mechanism for modulation of tumor immunity. More importantly, an antibody against PKM2 that disrupts the interaction between EcPKM2 and integrin αvβ3 is effective in converting M2 macrophages to M1 macrophages in tumors, suggesting a new therapeutic strategy and target for cancer therapies. Combination of the anti-PKM2 antibody with checkpoint blockades provides enhanced treatment effects.

Circulating immune cells play a crucial role in the anti-tumour immune response, yet the systemic immune system in metastatic breast cancers is not fully characterised. Investigating the cellular and molecular changes in peripheral blood mononuclear cells (PBMCs) from breast cancer patients could elucidate the role of circulating immune cells in metastasis and aid in identifying biomarkers for disease burden and progression.

In this study, we characterised the systemic immune landscape associated with varying levels of metastatic burden by analysing the single-cell transcriptomes of PBMCs from breast cancer patients and healthy controls. Our research focused on identifying changes in immune cell composition, transcriptional programs, and immune-cell communication networks linked to metastatic burden. Additionally, we compared these PBMC features onto a single-cell atlas of primary breast tumours to study corresponding traits in tumour-infiltrating immune cells.

In metastatic breast cancer, PBMCs exhibit a significant downregulation of the adaptive immune system and a decreased number and activity of unconventional T cells, such as γδ T cells. Additionally, metastatic burden is associated with impaired cell communication pathways involved in immunomodulatory functions. We also identified a gene signature derived from myeloid cells shared between tumour immune infiltrates and circulating immune cells in breast cancer patients.

Our study provides a comprehensive single-cell molecular profile of the peripheral immune system in breast cancer, offering a valuable resource for understanding metastatic disease in terms of tumour burden. By identifying immune traits linked to metastasis, we have unveiled potential new biomarkers of metastatic disease.

Although prior studies have reported a link between autoimmunity and carcinogenesis, the roles of genetic factors and potential mediators involved in this process remain elusive. We constructed disease-specific and combined polygenic risk scores (PRSs) for 6 common autoimmune diseases (AIDs) (systemic lupus erythematosus [SLE], rheumatoid arthritis, multiple sclerosis, Crohn's disease, ulcerative colitis [UC], and type 1 diabetes mellitus [T1D]) in the UK Biobank cohort. Compared to those without AID, AID patients at baseline had increased risks of overall cancer, hematological, digestive, and urinary cancer. The combined AID-PRS was significantly associated with increased risks of hematological cancer (HR [95% CI] per SD increase: 1.06 [1.03-1.09]) and non-Hodgkin's lymphoma (HR [95% CI] per SD increase: 1.10 [1.05-1.14]). For individual AID-PRSs, we identified 21 significant associations between 5 PRSs and 11 types of cancer in the overall population, along with 15 additional associations in the sex-stratified analysis. For example, SLE-, UC-, and T1D-PRS showed complex cross-cancer effects on risks of up to 6 cancer types. These associations were generally independent of immunosuppressant drug use. Differential associations of SLE-PRS with prostate cancer risk were found by prostate cancer PRS status ( P interaction <0.05). Several peripheral biomarkers, including red or white blood cell counts, platelet counts, and CRP partly mediated the PRS associations (up to 16.96%). Our study provides important insights into the role of autoimmune diseases in carcinogenesis, which also highlights opportunities for target cancer screening and prevention in potentially vulnerable populations.

Dysregulated cell movement is a hallmark of cancer progression and metastasis, the leading cause of cancer-related mortality. The metastatic cascade involves tumour cell migration, invasion, intravasation, dissemination, and colonisation of distant organs. These processes are influenced by reciprocal interactions between cancer cells and the tumour microenvironment (TME), including immune cells, stromal components, and extracellular matrix proteins. The epithelial-mesenchymal transition (EMT) plays a crucial role in providing cancer cells with invasive and stem-like properties, promoting dissemination and resistance to apoptosis. Conversely, the mesenchymal-epithelial transition (MET) facilitates metastatic colonisation and tumour re-initiation. Immune cells within the TME contribute to either anti-tumour response or immune evasion. These cells secrete cytokines, chemokines, and growth factors that shape the immune landscape and influence responses to immunotherapy. Notably, immune checkpoint blockade (ICB) has transformed cancer treatment, yet its efficacy is often dictated by the immune composition of the tumour site. Elucidating the molecular cross-talk between immune and cancer cells, identifying predictive biomarkers for ICB response, and developing strategies to convert cold tumours into immune-active environments is critical to overcoming resistance to immunotherapy and improving patient survival.

Cancer, being one of the most outrageous diseases, contributed to 48 % of the mortality in 2022, with lung cancer leading the race with a 12.4 % incidence rate. Conventional treatment modalities like radio-, chemo-, photo-, and immunotherapy employing nanocarriers often face several setbacks, such as non-specific delivery, off-site toxicity, rapid opsonization via the host immune system, and greater tumor recurrence rates. Moreover, the heterogeneous variability in the tumor microenvironment is responsible for existing therapy failure. With the advent of biomimetic nanoparticles as a novel and intriguing platform, researchers have exploited the inherent functionalities of the Cluster of Differentiation proteins (CD) as cell surface biomarkers and imparted the nanocarriers with enhanced homologous tumor targetability, immune evasion capability, and stealth properties, paving the way for improved therapy and diagnosis. This article explores pathogenesis and the multifaceted role of immune cells in non-small cell lung cancer. Moreover, the agenda of this article is to shed light on biomimetic nanoarchitectonics with respect to their fabrication, evaluation, and applications unraveling their synergistic effect with conventional therapies. Further discussion mentions the hurdles in clinical translation with viable solutions. The regulatory bottlenecks underscore the need for a regulatory roadmap with respect to commercialization. We believe that biomimetic nanoarchitectonics will be a beacon of hope in warfare against lung cancer.

Breast cancer (BC) is a global threat to female health. Sonodynamic therapy (SDT) has been shown to induce apoptosis in tumor cells and trigger immunogenic cell death, leading to the activation of antitumor immunity. However, the immunogenicity of this process may be compromised by oxidative stress and proteolysis. Necroptosis caused by ultrasound-targeted nanobubble destruction (UTND) could boost immunity. Therefore, we tested if necroptosis-inducible nanobubbles (NB) could enhance sonodynamic immunotherapy for BC. We also assessed whether O2-filled NB could address tumor hypoxia and enhance SDT efficacy.

A novel multifunctional nano-system, comprising NB for UTND encapsulating chlorin e6 (Ce6) for SDT and O2 for hypoxia alleviation was established. Ce6-O2NB cytocompatibility and intracellular uptake was studied in vitro, as well as whether Ce6-O2NB could generated reactive oxygen species when exposed to ultrasound irradiation in order to induce apoptosis in tumor cells. In vivo pharmacokinetics, therapeutic efficacy, and immune activation after Ce6-O2NB treatment were studied in 4T1 tumor-bearing mice.

Ce6-O2NB had a well-designed core-shell structure and desirable biocompatibility and safe therapeutic effects. Ce6-O2NB was able to load both ce6 and oxygen to increase ce6 and oxygen accumulation in tumors. After triggering by ultrasound, Ce6-O2NB generated reactive oxygen species (ROS) and acted as sonosensitizers for SDT, promoting tumor cell death through apoptotic and/or necrotic mechanisms. Furthermore, antitumor immunity was activated by stimulation of spleen lymphocyte proliferation and cytotoxicity, and increasing cytotoxic T lymphocyte numbers. Combination of oxygen with SDT ultimately strengthened its antitumor effects. In addition, Ce6-O2NB alleviated tumor hypoxia, induced increased ROS generation, and improved immune responses and therapeutic efficacy of SDT. Ce6-O2NB also facilitated fluorescence and contrast-enhanced ultrasound imaging.

Ce6-O2NB can mitigate tumor hypoxia, enhance SDT, and activate antitumor immunity by inducing simultaneous immunogenic apoptosis and necroptosis, ultimately activating antitumor immunity and inhibiting breast tumor growth in mice.

HCC, the most common form of liver cancer, is one of the leading causes of cancer-related deaths worldwide. Although the immune system plays a crucial role in liver cancer pathogenesis, the immune landscape within metabolic dysfunction-associated steatohepatitis-driven HCC remains poorly understood.

In this study, we used the high-fat, high-carbohydrate diet fed major urinary protein-urokinase-type plasminogen activator mouse model of metabolic dysfunction-associated steatohepatitis-driven HCC. We performed single-cell RNA sequencing on intrahepatic immune cells to characterize their heterogeneity and gene expression profiles. Additionally, we examined the role of B cells in antitumor immunity by depleting B cells in μMT mice and analyzing the effects on liver cancer progression.

Our analysis revealed significant shifts in intrahepatic immune cell populations, including B cells, T cells, and macrophages that undergo transcriptional reprogramming, suggesting altered roles in tumor immunity. Notably, an expanded subset of activated B cells in HCC mice showed an antitumor B cell gene expression signature associated with increased survival of patients with liver cancer. Consistently, B cell-deficient mice showed exacerbated liver cancer progression, a substantial reduction in intrahepatic lymphocytes, and impaired CD8+ T cell activation, suggesting that intrahepatic B cells may promote antitumor immunity by enhancing T cell responses.

Our findings reveal a complex immune reprogramming within the metabolic dysfunction-associated steatohepatitis-driven HCC microenvironment and underscore a protective role for B cells in liver cancer. These results highlight B cells as potential targets for immunomodulatory therapies in HCC.

Immunotherapy emerges as a promising approach, marked by recent substantial progress in elucidating how the host immune response impacts tumor development and its sensitivity to various treatments. Immune checkpoint inhibitors have revolutionized cancer therapy by unleashing the power of the immune system to recognize and eradicate tumor cells. Among these, inhibitors targeting the programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have garnered significant attention due to their remarkable clinical efficacy across various malignancies. This review delves into the mechanisms of action, clinical applications, and emerging therapeutic strategies surrounding PD-1/PD-L1 blockade. We explore the intricate interactions between PD-1/PD-L1 and other immune checkpoints, shedding light on combinatorial approaches to enhance treatment outcomes and overcome resistance mechanisms. Furthermore, we discuss the expanding landscape of immune checkpoint inhibitors beyond PD-1/PD-L1, including novel targets such as CTLA-4, LAG-3, TIM-3, and TIGIT. Through a comprehensive analysis of preclinical and clinical studies, we highlight the promise and challenges of immune checkpoint blockade in cancer immunotherapy, paving the way for future advancements in the field.

Mucosal-associated invariant T-cells (MAIT) have been associated with lung cancer and pulmonary infections. The treatment of patients with cancer or infections includes host-directed therapies (HDTs). MAIT play a role in shaping the 'milieu interne' in cancer and infections and this review addresses the biology of MAIT in pulmonary pathophysiology.

MAIT represent an attractive target for therapy in pulmonary malignancies and infections. T-cells are often difficult to exploit therapeutically due to the diversity of both T-cell receptor (TCR) repertoire and its ligandome. MAIT-cells are restricted by the major histocompatibility complex class I-related gene protein (MR1) that presents nondefined tumor-associated targets, bacterial products, vitamin and drug derivates. Due to their plasticity in gene expression, MAIT are able to conversely switch from IFN-γ to IL-17 production. Both cytokines play a key role in protective immune responses in infections and malignancies. MAIT-derived production of interleukin (IL)-17/TGF-β shapes the tumor micro-environment (TME), including tissue re-modelling leading to pulmonary fibrosis and recruitment of neutrophils. MAIT contribute to the gut-lung axis associated with clinical improved responses of patients with cancer to checkpoint inhibition therapy. MAIT are at the crossroad of HDTs targeting malignant and infected cells. Clinical presentations of overt inflammation, protective immune responses and tissue re-modeling are reviewed along the balance between Th1, Th2, Th9, and Th17 responses associated with immune-suppression or protective immune responses in infections.

MAIT shape the TME in pulmonary malignancies and infections. Drugs targeting the TME and HDTs affect MAIT that can be explored to achieve improved clinical results while curbing overt tissue-damaging immune responses.

Systemic adjuvant therapy is indicated in patients with high-risk, resected melanoma to reduce recurrence risk and potentially improve survival rates. Monoclonal antibodies (mAbs) target immune checkpoints and have made significant advances as systemic adjuvant therapies.

This review discusses the main clinical trials that tested adjuvant mAbs in resected high-risk melanoma, including anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) and anti-programmed cell death-1 (PD-1); in addition to newer immunotherapies being tested in the adjuvant setting, including anti-lymphocyte activation gene 3 (LAG-3). We also briefly discuss targeted therapies as an alternative choice. Moreover, we highlight the pros and cons of using mAbs in the adjuvant setting, the reported adverse events (AEs), and the quality of life impact. Finally, we report data related to biomarker studies tested in the context of these clinical trials.

Immune checkpoint inhibitors (ICIs) have been shown to significantly improve relapse-free survival (RFS) as adjuvant therapy for high-risk melanoma. The long-term impact on overall survival (OS) was demonstrated in two trials that tested ipilimumab as compared to placebo (EORTC18071) and interferon-α (ECOG-ACRIN E1609). Furthermore, emerging data with neoadjuvant therapy followed by surgery and adjuvant therapy utilizing ICIs have demonstrated improved outcomes in the management of locoregionally advanced disease when compared to upfront surgery followed by adjuvant therapy alone.

Head and neck squamous cell carcinoma (HNSCC) remains among the most aggressive malignancies with limited treatment options, especially in recurrent and metastatic cases. Despite advances in surgery, radiotherapy, chemotherapy, and immune checkpoint inhibitors, survival rates remain suboptimal due to tumor heterogeneity, immune evasion, and treatment resistance. In recent years, Chimeric Antigen Receptor (CAR) T-cell therapy has revolutionized hematologic cancer treatment by genetically modifying T cells to target tumor-specific antigens like CD19, CD70, BCMA, EGFR, and HER2, leading to high remission rates. Its success is attributed to precise antigen recognition, sustained immune response, and long-term immunological memory, though challenges like cytokine release syndrome and antigen loss remain. Notably, its translation to solid tumors, including HNSCC, faces significant challenges, such as tumor microenvironment (TME)-induced immunosuppression, antigen heterogeneity, and limited CAR T-cell infiltration. To address these barriers, several tumor-associated antigens (TAAs), including EGFR, HER2 (ErbB2), B7-H3, CD44v6, CD70, CD98, and MUC1, have been identified as potential CAR T-cell targets in HNSCC. Moreover, innovative approaches, such as dual-targeted CAR T-cells, armored CARs, and CRISPR-engineered modifications, aim to enhance efficacy and overcome resistance. Notably, combination therapies integrating CAR T-cells with immune checkpoint inhibitors (e.g., PD-1/CTLA-4 blockade) and TGF-β-resistant CAR T designs are being explored to improve therapeutic outcomes. This review aimed to elucidate the current landscape of CAR T-cell therapy in HNSCC, by exploring its mechanisms, targeted antigens, challenges, emerging strategies, and future therapeutic potential.

Gastric cancer (GC) exhibits high heterogeneity that relies on the oncogenic properties of cancer cells and multicellular interactions in the tumour microenvironment. However, the heterogeneity of GC and their molecular characteristics are still largely unexplored.

We employed single-cell and spatial transcriptomics to comprehensively map the intra-tumoural heterogeneity within GC. Additionally, in vitro experiments, clinical sample analyses, and patient-derived organoid models (PDOs) were conducted to validate the key interaction patterns between tumor cells and stromal cells.

Seven robust meta-programs (MP1-MP7) in GC were defined with distinct biological significance and spatial distributions. MP3 and MP4 were intimately associated with distinct CD8 T cells skewed toward a cytotoxic or exhaustion state, while MP7, characterised by the highest degree of malignancy, harboured an immune lockdown microenvironment around it and spatially associated with myofibroblasts (myCAFs). Notably, we clarified the interplay between the MP7 and myCAFs, where MP7 induces the chemotactic migration of fibroblasts and promoting their transformation into myCAFs via GDF15/TGFBR2, and in turn, myCAFs-derived RSPO3 up-regulates EGR1 to promote the transformation to MP7 in GC cells and human PDOs. Ultimately, the accumulation of myCAFs around MP7 led to fewer infiltration of CD8 T cells, resulting an immune-deprived microenvironment and the diminished efficacy of immunotherapy. Additionally, based on the gene expression signatures of MP7 GC cells, we predicted specific drugs and verified more potent inhibitory effects of Taselisib and Lapatinib for MP7 GC cells than conventional drugs at the same concentration.

Taken together, these results deepened the understanding of GC heterogeneity and paved the way for novel therapeutic strategies by targeting MP7 GC cells and their interaction loop with myCAFs in GC treatment.

Seven robust meta-programs (MP1-MP7) were identified in gastric cancer. MP7 was strongly correlated with cancer metastasis and poor survival of gastric cancer patients. MP7 promoted fibroblast transformation into myCAFs via GDF15/TGFBR2, creating an immune lockdown microenvironment. MyCAFs induced MP7 transformation via the RSPO3/EGR1 pathway, promoting gastric cancer cell migration. Taselisib and Lapatinib were potent inhibitors of MP7 GC cells.

Tumorigenesis ensues within a heterogeneous tissue microenvironment that promotes malignant transformation, metastasis and treatment resistance. A major feature of the tumor microenvironment is the heterogeneous population of cancer-associated fibroblasts and myeloid cells that stiffen the extracellular matrix. The heterogeneously stiffened extracellular matrix in turn activates cellular mechanotransduction and creates a hypoxic and metabolically hostile microenvironment. The stiffened extracellular matrix and elevated mechanosignaling also drive tumor aggression by fostering tumor cell growth, survival, and invasion, compromising antitumor immunity, expanding cancer stem cell frequency, and increasing mutational burden, which promote intratumor heterogeneity. Delineating the molecular mechanisms whereby tissue mechanics regulate these phenotypes should help to clarify the basis for tumor heterogeneity and cancer aggression and identify novel therapeutic targets that could improve patient outcome. Here, we discuss the role of the extracellular matrix in driving cancer aggression through its impact on tumor heterogeneity.

Background: The global burden of cancer necessitates innovative approaches to its management and treatment. Traditional treatments like radiotherapy, immunotherapy, surgery, and chemotherapy, carry significant side effects that impact patient quality of life. Dietary fiber has attracted research interest as a potential mitigator of cancer progression and a supportive agent in cancer treatment. This bibliometric study analyzes trends in research connecting dietary fiber, cancer therapy, and gut health from April 1999 to May 2024. Methods and Results: Web of Science, PubMed, and Scopus databases were used to retrieve peer-reviewed publications from April 1999 to May 2024 on dietary fiber and cancer management. The study identifies a rising scholarly interest in dietary fiber's role in cancer management, focusing significantly on the interactions between dietary fiber and gut microbiota. These interactions are particularly noted for their influence on inflammation and cancer metastasis. The study highlights evolving research themes, the importance of specific fiber types in cancer progression, and highlights persistent foundational themes like glycosylation. Emerging areas include personalized nutrition and innovative therapeutic approaches. The geographical and institutional contributions, mainly from the United States and China, underline the significance of collaborative and interdisciplinary efforts in advancing research. Conclusion: This analysis emphasizes integrating dietary strategies in comprehensive cancer care and aims to address research gaps to develop more effective and patient-centered cancer therapy and prevention strategies.

The interplay between tumor cells and the microenvironment significantly influences cancer progression. Here, we report a significant role of the transcription factor FOXM1 in shaping the tumor immune landscape. Single-cell sequencing reveals that tumor-intrinsic FOXM1 creates an immune-suppressive tumor microenvironment by inhibiting expression of stress ligands (including ULBP1) on cancer cells, thereby blocking NKG2D-NKG2DL interactions critical for priming natural killer- and T cell-mediated cytotoxicity of cancer cells. FOXM1 suppresses ULBP1 expression by epigenetically silencing the DNA-sensing protein STING using a DNMT1-UHRF1 complex, which in turn inhibits the unfolded protein response protein CHOP from activating ULBP1. Importantly, cancer patients with higher levels of FOXM1 and DNMT1, and lower levels of STING and ULBP1, have worse survival and are less responsive to immunotherapy. Collectively, our findings provide key insight into how a tumor-intrinsic transcription factor epigenetically shapes the tumor immune microenvironment, with strong implications for refining existing and designing new cancer immunotherapies.

Neoantigen-based immunotherapy has emerged as a transformative approach in cancer treatment, offering precision medicine strategies that target tumor-specific antigens derived from genetic, transcriptomic, and proteomic alterations unique to cancer cells. These neoantigens serve as highly specific targets for personalized therapies, promising more effective and tailored treatments. The aim of this article is to explore the advances in neoantigen-based therapies, highlighting successful treatments such as vaccines, tumor-infiltrating lymphocyte (TIL) therapy, T-cell receptor-engineered T cells therapy (TCR-T), and chimeric antigen receptor T cells therapy (CAR-T), particularly in cancer types like glioblastoma (GBM). Advances in technologies such as next-generation sequencing, RNA-based platforms, and CRISPR gene editing have accelerated the identification and validation of neoantigens, moving them closer to clinical application. Despite promising results, challenges such as tumor heterogeneity, immune evasion, and resistance mechanisms persist. The integration of AI-driven tools and multi-omic data has refined neoantigen discovery, while combination therapies are being developed to address issues like immune suppression and scalability. Additionally, the article discusses the ongoing development of personalized immunotherapies targeting tumor mutations, emphasizing the need for continued collaboration between computational and experimental approaches. Ultimately, the integration of cutting-edge technologies in neoantigen research holds the potential to revolutionize cancer care, offering hope for more effective and targeted treatments.

The potential role of immune cells and the precise contributions of genes from various immune cells in the development of colorectal cancer (CRC) remains unclear. We aimed to investigate the potential causal relationships between specific immune cell genes and the development of CRC by performing Mendelian randomization (MR) analysis.

The cis-expression quantitative trait loci (eQTLs) data for type-specific immune cells were used to perform MR analysis. Outcomes data were obtained from the latest Genome Wide Association Studies (GWAS), comprising 78,473 European ancestry CRC cases and 107,143 controls. A few sensitivity analyses, encompassing pleiotropy and colocalization analyses, along with the application of False Discovery Rate (FDR) correction, were carried out to mitigate potential biases.

A total of 395 genes were found to be associated with CRC. After FDR correction, a total of 47 genes across 14 immune cell types were identified. Notably, the FHL3 gene showed the strongest association with CRC in multiple immune cell types, including CD4 + naïve and central memory T cells (CD4NC), CD4 + T cells with an effector memory or central memory phenotype (CD4ET), CD8 + naïve and central memory T cells (CD8NC), CD8 + T cells with an effector memory phenotype (CD8ET), and NK recruiting cells (NKR). Sensitivity analyses and pleiotropy assessments excluded the bias due to weak instruments and linkage disequilibrium. Additionally, the associations were supported by strong evidence of colocalization with CRC. The expression of FHL3 in normal tissue was higher than that in the tumor tissue at the mRNA expression and single-cell levels, and low mRNA expression of FHL3 was associated with shorter survival time in CRC patients.

Our study provides a novel perspective on the potential causal link between the low expression of FHL3 gene and the risk of CRC. More evidence is essential to further reveal the biological mechanisms underlying this association.