The efficacy of primary tumor resection (PTR) for colorectal cancer lung metastases (CRLM) is unclear. This study used the SEER database to investigate if PTR improves prognosis in CRLM patients and developed a nomogram to predict the likelihood of benefiting from PTR.

Patients with CRLM from the SEER database (2010-2019) were included. Propensity score matching (PSM) balanced PTR and non-PTR groups. Kaplan-Meier analysis compared overall and cancer-specific survival. Cox regression identified survival factors. The PTR group was divided into training and validation sets (7:3 ratio) for nomogram development using logistic regression. Nomogram performance was validated using ROC curves, calibration curves, and decision curve analysis.

A total of 3264 CRLM patients were included (2459 with PTR, 805 without). After 1:1 PSM, each group had 484 patients. PTR significantly improved survival (p < 0.001). Logistic regression identified age, race, T-stage, chemotherapy, and metastases to the liver, brain, and bone as risk factors. The nomogram showed excellent predictive performance and clinical utility.

PTR improves survival in CRLM patients, and the nomogram effectively predicts the benefit of PTR.

Neoadjuvant concurrent chemoradiotherapy (CCRT) is routinely used before surgery in patients with locally advanced rectal cancer to reduce tumor size and decrease the risk of local recurrence. However, the disease-specific survival has not improved in most cases due to distant metastases. In selected individuals exhibiting a clinical complete response, non-operative management may be allowed; however, those who presented no or little response tend to have an inferior prognosis. Consequently, refined molecular characterization could aid in predicting which patients would benefit from neoadjuvant chemoradiotherapy.

The mRNA level (by transcriptomic profiling) and protein expression (by immunohistochemical staining) of C-X-C motif chemokine ligand 11 (CXCL11) were integrated to predict neoadjuvant chemoradiotherapy efficacy. For survival analysis, clinicopathological features and CXCL11 immunoreactivity that were statistically significant in univariate analysis were included in multivariate analysis using the Cox proportional hazards regression model.

We identified that the CXCL11 level exhibits the most significant downregulation among neoadjuvant chemoradiotherapy non-responders. Using tumor samples from our rectal cancer cohort (n = 343) with immunohistochemistry validation, we demonstrated that low CXCL11 immunoexpression shows significant correlations with advanced disease and positive lymph nodes both prior to and following CCRT (all p < 0.001), vascular and perineural invasion (p < 0.001 and p = 0.006), and poor response to CCRT (p < 0.001). Moreover, low CXCL11 immunoexpression was an independent adverse prognostic factor significantly associated with patient survival. Additionally, we further identified pyroptotic cell death as an unrevealed role of CXCL11 in rectal cancer through bioinformatic analysis.

CXCL11 expression may serve as an early predictor of clinical outcomes and aid in therapeutic decision-making by identifying individuals likely to respond to neoadjuvant chemoradiotherapy in rectal cancer.

Programmed necrosis, a controlled cell death method that bypasses resistance mechanisms that render apoptosis ineffective, is a potential cancer treatment target. Due to their diverse biological activities and low side effects, natural products are being explored as modulators of programmed necrosis pathways. This review highlights the potential of natural compounds to target cancer cells while preserving healthy tissues and their interaction with essential programmed necrosis mechanisms like ferroptosis and necroptosis. Recent developments have identified various types of programmable necrosis, including necroptosis, ferroptosis, pyroptosis, proptosis, mitochondrial permeability transition-driven necrosis, and oncosis. Natural compounds are increasingly being utilized as a primary source of anti-cancer medications, providing new cancer treatments. This review demonstrates the molecular mechanisms behind lipid peroxidation, mixed lineage kinase domain-like protein, and receptor-interacting protein kinases (RIPK1 and RIPK3) inducing cell death. Recent research has identified natural compounds like polyphenols, alkaloids, and terpenoids that can modulate pathways and benefit preclinical cancer models. The review underscores the potential of natural compounds in developing innovative cancer treatments by integrating pharmacology and cellular signaling knowledge. Integrating natural compound studies and programmed necrosis research presents a promising avenue for oncologists to overcome treatment resistance. Natural compounds have shown potential in developing programmed necrosis as a novel cancer treatment approach, enhancing therapeutic effectiveness and minimizing side effects through preclinical research, pharmacology, and molecular biology.

Immune evasion by cancer cells involves reshaping the tumor microenvironment (TME) via communication with non-malignant cells. However, resistance-promoting interactions during treatment remain lesser known. Here we examine the composition, communication, and phenotypes of tumor-associated cells in serial biopsies from stage II and III high-risk estrogen receptor positive (ER+ ) breast cancers of patients receiving endocrine therapy (letrozole) as single agent or in combination with ribociclib, a CDK4/6-targeting cell cycle inhibitor. Single-cell RNA sequencing analyses on longitudinally collected samples show that in tumors overcoming the growth suppressive effects of ribociclib, first cancer cells upregulate cytokines and growth factors that stimulate immune-suppressive myeloid differentiation, resulting in reduced myeloid cell- CD8 + T-cell crosstalk via IL-15/18 signaling. Subsequently, tumors growing during treatment show diminished T-cell activation and recruitment. In vitro, ribociclib does not only inhibit cancer cell growth but also T cell proliferation and activation upon co-culturing. Exogenous IL-15 improves CDK4/6 inhibitor efficacy by augmenting T-cell proliferation and cancer cell killing by T cells. In summary, response to ribociclib in stage II and III high-risk ER +  breast cancer depends on the composition, activation phenotypes and communication network of immune cells.

The occurrence and progression of traumatic brain injury involve a complex process. The pathophysiological mechanisms triggered by neuronal damage include various forms of programmed cell death, including ferroptosis. We observed upregulation of TNFAIP3 in mice after traumatic brain injury. Overexpression of TNFAIP3 inhibits HT-22 proliferation and cell viability through ferroptosis. Mechanistically, TNFAIP3 interacts with the HMOX1 protein and promotes its stability through the deubiquitination pathway. Additionally, TNFAIP3 can enhance lipoperoxidation, mitochondrial damage, and neuronal cell death by promoting ACSL3 degradation via NEDD4-mediated ubiquitination. Mice injected with AAV-shTNFAIP3 exhibited reduced neuronal degeneration and improved motor and cognitive function following cortical impact injury. In conclusion, our findings demonstrate that TNFAIP3 deficiency inhibits neuronal cell ferroptosis and ameliorates cognitive impairment caused by traumatic brain injury and demonstrate its potential applicability in the treatment of traumatic brain injury.

DNA logic gates with dynamic nanostructures have made a profound impact on cancer diagnosis and treatment. Through programming the dynamic structure changes of DNA nanodevices, precise molecular recognition with signal amplification and smart therapeutic strategies have been reported. This enhances the specificity and sensitivity of cancer theranostics, and improves diagnosis precision and treatment outcomes. This review explores the basic components of dynamic DNA nanostructures and corresponding DNA logic gates, as well as their applications for cancer diagnosis and therapies. The dynamic DNA nanostructures would contribute to cancer early detection and personalized treatment.

T follicular helper (TFH) cells, a subset of CD4+Th cells, play a critical role in B cell activation, proliferation, and differentiation primarily within B follicles in secondary lymphoid organs, essential processes for effective antibody responses. TFH cells are also implicated in various conditions, including autoimmune diseases, cancer, infectious diseases, allergies, and vaccine reactions. Despite their broad impact, a review of the literature on TFH cells and tumors has not been conducted. We aimed to fill this gap by providing a detailed analysis of the research landscape concerning TFH cells and tumors.

We conducted a bibliometric analysis of literature on TFH cells and tumors from 2012 to 2024 using the Web of Science Core Collection (WoSCC). For an analysis of the global research landscape, we employed VOSviewer (version 1.6.20), CiteSpace 6.2.R6 software, and the "bibliometric" package in R language (version 4.3.2) to evaluate data on countries/regions, authors and cited authors, institutions, journals, references, and keywords. We also conducted a systematic review to summarize the global research trends, prospects, and hotspots in this field.

Our analysis included contributions from 60 countries/regions, 7,864 authors, 35,853 cited authors, 1,756 institutions, 385 academic journals, 50883 references, 222 keywords, and 1,181published papers. Over the past decade, the volume of research on TFH cells and tumors had consistently increased. China published the most papers, more than double that of the United States. The top 2 authors ranked by publication volume were Gaulard, Philippe (14 articles, 379 citations), and De leval, Laurence (12 articles, 236 citations) Notably, 9 of the top 10 most published institutions were from China. Frontiers in Immunology and Immunity were the leading journals in publications and citations. A cluster analysis revealed a shift in research focus from "expression","B cells" and "survival" to "tumor microenvironment", "tumor infiltrating immune cells" and "immune infiltration" in recent years.

This bibliometric analysis suggests that TFH cells hold significant research value and potential clinical applications in tumor immunotherapy. Moreover, the bibliometric analysis offers valuable references and guidance for related research endeavors. It also points out the prevailing issues and challenges in TFH cell research, and underscores the need for further basic and clinical research to advance the related fields.

The polymorphic microbiome is considered a new hallmark of cancer. Advances in High-Throughput Sequencing have fostered rapid developments in microbiome research. The interaction between cancer cells, immune cells, and microbiota is defined as the immuno-oncology microbiome (IOM) axis. Fungal microbes (the mycobiome), although representing only ∼ 0.1-1% of the microbiome, are a critical immunologically active component of the tumor microbiome. Accumulating evidence suggests a possible involvement of commensal and pathogenic fungi in cancer initiation, progression, and treatment responsiveness. The tumor-associated mycobiome mainly consists of the gut mycobiome, the oral mycobiome, and the intratumoral mycobiome. However, the role of fungi in cancer remains poorly understood, and the diversity and complexity of analytical methods make it challenging to access this field. This review aims to elucidate the causal and complicit roles of mycobiome in cancer development and progression while highlighting the issues that need to be addressed in executing such research. We systematically summarize the advantages and limitations of current fungal detection and analysis methods. We enumerate and integrate these recent findings into our current understanding of the tumor mycobiome, accompanied by the prospect of novel and exhilarating clinical implications.

The systemic immune-inflammation index (SII) has emerged as a promising prognostic marker in various malignancies. However, its prognostic significance in patients with small-cell lung cancer (SCLC) treated with immune checkpoint inhibitors (ICIs) remains unclear. In this study, we evaluated the prognostic impact of the SII in patients with SCLC after ICI use.

Of 62 patients with SCLC who received chemoimmunotherapy at our institution between September 2019 and July 2024, we retrospectively analyzed 36 patients who subsequently received ICI maintenance therapy following the initial chemoimmunotherapy treatment. The SII was calculated at the start of the second cycle of the ICI maintenance therapy. Patients were stratified into high (≥ 570) and low (< 570) SII groups. Overall survival (OS) and progression-free survival (PFS) were compared between the groups using the Kaplan-Meier method and log-rank test. Multivariate analysis using the Cox proportional hazards model was performed to identify independent prognostic factors.

The high SII group exhibited a significantly shorter OS (median 12.1 vs. 24.1 months, P = 0.010) and PFS (median 5.2 vs. 8.1 months, P = 0.026) than those in the low SII group. A multivariate analysis identified SII ≥ 570 as an independent negative prognostic factor for OS (hazard ratio 3.83, 95% confidence interval 1.38-10.6, P = 0.010).

Elevated SII in the initial phase of ICI maintenance therapy was associated a with poor prognosis in patients with SCLC, supporting its utility as a prognostic biomarker in this setting. Therefore, prospective validation is required to confirm these findings.

Digestive tract carcinomas are the most commonly occurring cancers worldwide, but their prognosis with traditional treatments remains poor. T lymphocytes are well-recognized as crucial components of effective anti-tumor immunity, and current immunotherapeutic strategies concentrate mainly on T-cell-mediated immunity reinforcement, whereas the role of B lymphocytes and plasma cells (PCs) has been neglected in the past, and it is only recently that these cells have been considered as key players in the tumor microenvironment (TME). In this review, we describe the complex dual role of B lymphocytes and PCs in promoting and inhibiting tumor progression in the TME of digestive tract carcinomas, and we demonstrate their prognostic value. Furthermore, we highlight their controversial function in cancer and nominate them as additional therapeutic targets for the development of new treatment interventions that might alter the dismal prognosis of digestive tract tumors.

Although immunotherapy has revolutionized cancer treatment, its efficacy is affected by multiple factors, particularly those derived from the complexity and heterogeneity of the tumor-immune microenvironment (TIME). Strategies that simultaneously and synergistically engage multiple immune cells in TIME remain highly desirable but challenging. Herein, we report a multimodal and programmable platform that enables the integration of multiple therapeutic modules into single agents for tumor-targeted co-engagement of multiple immune cells within TIME. We developed the triple orthogonal linker (T-Linker) technology to integrate various therapeutic small molecules and biomolecules as multimodal targeting chimeras (Multi-TACs). The EGFR-CD3-PDL1 Multi-TAC facilitated T-dendritic cell co-engagement to target solid tumors with excellent efficacy, as demonstrated in vitro, in several humanized mouse models and in patient-derived tumor models. Furthermore, Multi-TACs were constructed to coordinate T cells with other immune cell types. The highly modular and programmable feature of our Multi-TACs may find broad applications in immunotherapy and beyond.

No established method currently exists for evaluating tumor-infiltrating lymphocytes (TILs) in gastric cancer (GC), and their clinical significance based on infiltration site in GC remains unclear. In this study, we developed a method to evaluate TILs according to their infiltration site as a prognostic marker for GC. We retrospectively analyzed 103 patients with advanced GC who underwent curative resection. TILs located at the invasive margin (TILIM) and the center of tumors (TILCT) were scored semi-quantitatively using immunohistochemical staining of CD8+ T cells. The sum of the TILIM and TILCT scores was defined as the TILs score. Based on this score, patients were classified into low and high TILs groups. Quantitative TILs were also assessed to validate the semi-quantitative scoring method. Furthermore, we confirmed a tumor suppressive effect due to CD8+ T cells co-cultured in GC cell lines in vitro. In the univariate analysis, patients with low TILIM were significantly more likely to be female, younger, and have undifferentiated histological types and deeper tumor invasion compared to those with high TILIM. Similarly, patients with low TILCT had significantly more positive lymph node metastases than those with high TILCT. In the multivariate analysis, deeper tumor invasion and positive lymph node metastasis were identified as independent risk factors for patients with low TILIM and low TILCT, respectively. According to our semi-quantitative TILs scoring method, the low TILs group had significantly poorer prognoses compared to the high TILs group. This group had significantly larger tumor diameters, deeper tumor invasion, and more positive lymph node metastases. Additionally, deeper tumor invasion was an independent risk factor for the low TILs group. Quantitative TILs analysis revealed that the low TILs group had significantly lower TIL levels compared to the high TILs group. In vitro, CD8+ T cells induced apoptosis in GC cells in a concentration-dependent manner. Furthermore, these cells significantly suppressed the proliferative, migratory, and invasive capacities of GC cells. Our simple and versatile semi-quantitative scoring method for CD8+ TILs indicates that CD8+ TILs are sensitive prognostic markers. The low TILs group accurately reflects the low quantitative TIL levels and is associated with poor oncological prognosis.

Breast cancer is a leading cause of cancer-related mortality among women worldwide, necessitating the identification of reliable prognostic markers to guide treatment and improve patient outcomes. Recent research has highlighted the prognostic significance of tumor-infiltrating lymphocytes (TILs) in breast cancer, with high levels of TILs being associated with improved survival rates and better responses to therapy. This review delves into the mechanisms driving lymphocyte infiltration, its clinical implications, and the potential for TILs to serve as predictive biomarkers in breast cancer management. The presence of TILs within the tumor microenvironment reflects a dynamic interplay between tumor cells and the host immune system. Chemokine signaling, antigen presentation, and immune checkpoint interactions are key mechanisms that facilitate the recruitment and activity of lymphocytes at the tumor site. Clinically, the density of TILs varies across breast cancer subtypes, with the most significant prognostic value observed in triple-negative and HER2-positive breast cancers. High TIL levels correlate with improved overall survival and disease-free survival, underscoring their potential as a valuable prognostic indicator. Therapeutically, the role of TILs has opened new avenues in breast cancer treatment, particularly in the realm of immunotherapy. Immune checkpoint inhibitors, adoptive cell therapy, and combination therapies leveraging TILs are being explored to enhance antitumor responses. As research progresses, the integration of TIL assessment into routine clinical practice could revolutionize personalized treatment strategies, ultimately improving prognostic accuracy and patient outcomes in breast cancer care.

The field of immunology is fundamental to our understanding of the intricate dynamics of the tumor microenvironment. In particular, tumor-infiltrating lymphocyte (TIL) assessment emerges as essential aspect in breast cancer cases. To gain comprehensive insights, the quantification of TILs through computer-assisted pathology (CAP) tools has become a prominent approach, employing advanced artificial intelligence models based on deep learning techniques. The successful recognition of TILs requires the models to be trained, a process that demands access to annotated datasets. Unfortunately, this task is hampered not only by the scarcity of such datasets, but also by the time-consuming nature of the annotation phase required to create them. Our review endeavors to examine publicly accessible datasets pertaining to the TIL domain and thereby become a valuable resource for the TIL community. The overall aim of the present review is thus to make it easier to train and validate current and upcoming CAP tools for TIL assessment by inspecting and evaluating existing publicly available online datasets.

Neuroblastoma exhibits substantial heterogeneity, which is intricately linked to various genetic alterations. We aimed to explore immune status in the peripheral blood and prognosis of patients with neuroblastoma with different genetic characteristics.

We enrolled 31 patients with neuroblastoma and collected samples to detect three genetic characteristics. Peripheral blood samples were tested for immune cells and cytokines by fluorescent microspheres conjugated with antibodies and flow cytometry. Event-free survival (EFS) was analyzed using the Kaplan‒Meier method.

Twenty-two patients had genetic aberrations, including MYCN amplification in 6 patients, chromosome 1p deletion in 9 patients, and chromosome 11q deletion in 14 patients. Two genetic alterations were present in seven patients. The EFS was worse in patients with MYCN amplification or 1p deletion than in the corresponding group, whereas 11q deletion was a prognostic factor only in patients with unamplified MYCN. Changes in immune status revealed a decrease in the proportion of T cells in blood, and an increase in regulatory T cells and immunosuppression-related cytokines such as interleukin (IL)-10. The EFS of the IL-10 high-level group was lower than that of the low-level group. Patients with concomitant genetic alterations and a high level of IL-10 had worse EFS than other patients.

Patients with neuroblastoma characterized by these genetic characteristics often have suppressed T cell response and an overabundance of immunosuppressive cells and cytokines in the peripheral blood. This imbalance is significantly associated with poor EFS. Moreover, if these patients show an elevated levels of immunosuppressive cytokines such as IL-10, the prognosis will be worse.

The establishment and utilization of preclinical animal models constitute a pivotal aspect across all facets of cancer research, indispensably contributing to the comprehension of disease initiation and progression mechanisms, as well as facilitating the development of innovative anti-cancer therapeutic approaches. These models have emerged as crucial bridges between basic and clinical research, offering multifaceted support to clinical investigations. This study initially focuses on the importance and benefits of establishing preclinical animal models, discussing the different types of preclinical animal models and recent advancements in cancer research. It then delves into cancer treatment, studying the characteristics of different stages of tumor development and the development of anti-cancer drugs. By integrating tumor hallmarks and preclinical research, we elaborate on the path of anti-cancer drug development and provide guidance on personalized cancer therapy strategies, including synthetic lethality approaches and novel drugs widely adopted in the field. Ultimately, we summarize a strategic framework for selecting preclinical safety experiments, tailored to experimental modalities and preclinical animal species, and present an outlook on the prospects and challenges associated with preclinical animal models. These models undoubtedly offer new avenues for cancer research, encompassing drug development and personalized anti-cancer protocols. Nevertheless, the road ahead continues to be lengthy and fraught with obstacles. Hence, we encourage researchers to persist in harnessing advanced technologies to refine preclinical animal models, thereby empowering these emerging paradigms to positively impact cancer patient outcomes.

The presence of tertiary lymphoid structures (TLSs) associated with distinct treatment efficacy and clinical prognosis has been identified in various cancer types. However, the mechanistic roles and clinical implications of TLSs in genitourinary (GU) cancers remain incompletely explored. Despite their potential role as predictive markers described in numerous studies, it is essential to comprehensively evaluate the characteristics of TLSs, including drivers of formation, structural foundation, cellular compositions, maturation stages, molecular features, and specific functionality to maximize their positive impacts on tumor-specific immunity. The unique contributions of these structures to cancer progression and biology have fueled interest in these structures as mediators of antitumor immunity. Emerging data are trying to explore the effects of therapeutic interventions targeting TLSs. Therefore, a better understanding of the molecular and phenotypic heterogeneity of TLSs may facilitate the development of TLSs-targeting therapeutic strategies to obtain optimal clinical benefits for GU cancers in the setting of immunotherapy. In this review, the authors focus on the phenotypic and functional heterogeneity of TLSs in cancer progression, current therapeutic interventions targeting TLSs and the clinical implications and therapeutic potential of TLSs in GU cancers.

Obesity and gastric cancer (GC) are prevalent diseases worldwide. In particular, the number of patients with obesity is increasing annually, while the incidence and mortality rates of GC are ranked high. Consequently, these conditions seriously affect the quality of life of individuals. While evidence suggests a strong association between these two conditions, the underlying mechanisms of this comorbidity remain unclear.

We obtained the gene expression profiles of GSE94752 and GSE54129 from the Gene Expression Omnibus database. To investigate the associated biological processes, pathway enrichment analyses were conducted using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes for the shared differentially expressed genes in obesity and GC. A protein-protein interaction (PPI) network was subsequently established based on the Search Tool for the Retrieval of Interacting Genes (STRING) database, followed by the screening of the core modules and central genes in this network using Cytoscape plug-in MCODE. Furthermore, we scrutinized the co-expression network and the interplay network of transcription factors (TFs), miRNAs, and mRNAs linked to these central genes. Finally, we conducted further analyses using different datasets to validate the significance of the hub genes.

A total of 246 shared differentially expressed genes (209 upregulated and 37 downregulated) were selected for ensuing analyses. Functional analysis emphasized the pivotal role of inflammation and immune-associated pathways in these two diseases. Using the Cytoscape plug-in CytoHubba, nine hub genes were identified, namely, CXCR4, CXCL8, CXCL10, IL6, TNF, CCL4, CXCL2, CD4, and CCL2. IL6 and CCL4 were confirmed as the final hub genes through validation using different datasets. The TF-miRNA-mRNA regulatory network showed that the TFs primarily associated with the hub genes included RELA and NFKB1, while the predominantly associated miRNAs included has-miR-195-5p and has-miR-106a-5p.

Using bioinformatics methods, we identified two hub genes from the Gene Expression Omnibus datasets for obesity and GC. In addition, we constructed a network of hub genes, TFs, and miRNAs, and identified the major related TFs and miRNAs. These factors may be involved in the common molecular mechanisms of obesity and GC.

Breast cancer poses a global health challenge, yet the influence of ethnicity on the tumor microenvironment (TME) remains understudied. In this investigation, we examined immune cell infiltration in 230 breast cancer samples, emphasizing diverse ethnic populations. Leveraging tissue microarrays (TMAs) and core samples, we applied multiplex immunofluorescence (mIF) to dissect immune cell subtypes across TME regions. Our analysis revealed distinct immune cell distribution patterns, particularly enriched in aggressive molecular subtypes triple-negative and HER2-positive tumors. We observed significant correlations between immune cell abundance and key clinicopathological parameters, including tumor size, lymph node involvement, and patient overall survival. Notably, immune cell location within different TME regions showed varying correlations with clinicopathologic parameters. Additionally, ethnicities exhibited diverse distributions of cells, with certain ethnicities showing higher abundance compared to others. In TMA samples, patients of Chinese and Caribbean origin displayed significantly lower numbers of B cells, TAMs, and FOXP3-positive cells. These findings highlight the intricate interplay between immune cells and breast cancer progression, with implications for personalized treatment strategies. Moving forward, integrating advanced imaging techniques, and exploring immune cell heterogeneity in diverse ethnic cohorts can uncover novel immune signatures and guide tailored immunotherapeutic interventions, ultimately improving breast cancer management.

In recent years, there has been an observed increase in the frequency of cutaneous carcinoma, which correlates with sun exposure. This study aims to explore the variances of tumor characteristics and immune response markers among patients diagnosed with cutaneous squamous-cell carcinoma (SCC) and basosquamous-cell carcinoma (BSC) with varying levels of sun exposure. The objective is to elucidate the potential influence of sun exposure on tumor progression and immune response in these types of carcinomas. We conducted a retrospective observational study that included 132 patients diagnosed with SCC and BSC. Participants were separated into high- and low-sun exposure groups. Tumor characteristics and immune response markers, including lymphocyte percentage (LY%), neutrophil-to-lymphocyte ratio (NLR), and lymphocyte-to-monocyte ratio (LMR), were assessed using the Mann-Whitney U test. Our findings revealed the interplay between sun exposure, inflammation, aging, and immune response. In 80% of cases, it was found that individuals had high sun exposure throughout their lifetime. Patients in the high sun exposure category had a significantly higher LY% than those with low sun exposure (24.22 ± 7.64 vs. 20.71 ± 8.10, p = 0.041). Also, the NLR was lower in patients with high sun exposure (3.08 ± 1.47 vs. 3.94 ± 2.43, p = 0.023). Regarding inflammatory markers, the erythrocyte sedimentation rate (ESR), LY%, NLR, and LMR showed significant differences between the two groups. Patients who were diagnosed with SCC had higher ESR values (p = 0.041), higher LY% (p = 0.037), higher NLR (p = 0.041), and lower LMR (p = 0.025). This study provides evidence supporting distinct tumor characteristics and immune response patterns in patients diagnosed with SCC and BSC with a high sun exposure history. These findings imply that sun exposure may contribute to tumor progression and influence the immune response in individuals with SCC and BSC.

Lung cancer, acknowledged as one of the most fatal cancers globally, faces limited treatment options on an international scale. The success of clinical treatment is impeded by challenges such as late diagnosis, restricted treatment alternatives, relapse, and the emergence of drug resistance. This predicament has led to a saturation point in lung cancer treatment, prompting a rapid shift in focus towards the tumor microenvironment (TME) as a pivotal area in cancer research. Within the TME, Interleukin-1 (IL-1) is abundantly present, originating from immune cells, tissue stromal cells, and tumor cells. IL-1's induction of pro-inflammatory mediators and chemokines establishes an inflammatory milieu influencing tumor occurrence, development, and the interaction between tumors and the host immune system. Notably, IL-1 expression in the TME exhibits characteristics such as staging, tissue specificity, and functional pluripotency. This comprehensive review aims to delve into the impact of IL-1 on lung cancer, encompassing aspects of occurrence, invasion, metastasis, immunosuppression, and immune surveillance. The ultimate goal is to propose a novel treatment approach, considering the intricate dynamics of IL-1 within the TME.

An effective cancer therapy requires killing cancer cells and targeting the tumor microenvironment (TME). Searching for molecules critical for multiple cell types in the TME, we identified NR4A1 as one such molecule that can maintain the immune suppressive TME. Here, we establish NR4A1 as a valid target for cancer immunotherapy and describe a first-of-its-kind proteolysis-targeting chimera (PROTAC, named NR-V04) against NR4A1. NR-V04 degrades NR4A1 within hours in vitro and exhibits long-lasting NR4A1 degradation in tumors with an excellent safety profile. NR-V04 inhibits and frequently eradicates established tumors. At the mechanistic level, NR-V04 induces the tumor-infiltrating (TI) B cells and effector memory CD8+ T (Tem) cells and reduces monocytic myeloid-derived suppressor cells (m-MDSC), all of which are known to be clinically relevant immune cell populations in human melanomas. Overall, NR-V04-mediated NR4A1 degradation holds promise for enhancing anticancer immune responses and offers a new avenue for treating various types of cancers such as melanoma.

Carbon-based quantum dots (CQDs) have been shown to have promising application value in tumor diagnosis. Their use, however, is severely hindered by the complicated nature of the nanostructures in the CQDs. Furthermore, it seems impossible to formulate the mechanisms involved using the inadequate theoretical frameworks that are currently available for CQDs. In this review, we re-consider the structure-property relationships of CQDs and summarize the current state of development of CQDs-based tumor diagnosis based on biological theories that are fully developed. The advantages and deficiencies of recent research on CQDs-based tumor diagnosis are thus explained in terms of the manifestation of nine essential changes in cell physiology. This review makes significant progress in addressing related problems encountered with other nanomaterials.

Pathway analysis, including nontopology-based (non-TB) and topology-based (TB) methods, is widely used to interpret the biological phenomena underlying differences in expression data between two phenotypes. By considering dependencies and interactions between genes, TB methods usually perform better than non-TB methods in identifying pathways that include closely relevant or directly causative genes for a given phenotype. However, most TB methods may be limited by incomplete pathway data used as the reference network or by difficulties in selecting appropriate reference networks for different research topics. Here, we propose a gene set correlation enrichment analysis method, Gscore, based on an expression dataset-derived coexpression network to examine whether a differentially expressed gene (DEG) list (or each of its DEGs) is associated with a known gene set. Gscore is better able to identify target pathways in 89 human disease expression datasets than eight other state-of-the-art methods and offers insight into how disease-wide and pathway-wide associations reflect clinical outcomes. When applied to RNA-seq data from COVID-19-related cells and patient samples, Gscore provided a means for studying how DEGs are implicated in COVID-19-related pathways. In summary, Gscore offers a powerful analytical approach for annotating individual DEGs, DEG lists, and genome-wide expression profiles based on existing biological knowledge.

Existing studies on the relationship between tea intake and lung diseases have yielded inconsistent results, leading to an ongoing dispute on this issue. The impact of tea consumption on the respiratory system remained elucidating.

We conducted a two-sample Mendelian randomization (MR) study to evaluate the associations between five distinct tea intake phenotypes and 15 different respiratory outcomes using open Genome-wide association study (GWAS) data. The inverse variance weighted (IVW) was used for preliminary screening and a variety of complementary methods were used as sensitivity analysis to validate the robustness of MR estimates. Pathway enrichment analysis was used to explore possible mechanisms.

IVW found evidence for a causal effect of standard tea intake on an increased risk of lung squamous cell cancer (LSCC) (OR = 1.004; 95% CI = 1.001-1.007; P = 0.00299). No heterogeneity or pleiotropy was detected. After adjustment for potential mediators, including smoking, educational attainment, and time spent watching television, the association was still robust in multivariable MR. KEGG and GO enrichment predicted proliferation and activation of B lymphocytes may play a role in this causal relation. No causalities were observed when evaluating the effect of other kinds of tea intake on various pulmonary diseases.

Our MR estimates provide causal evidence of the independent effect of standard tea intake (black tea intake) on LSCC, which may be mediated by B lymphocytes. The results implied that the population preferring black tea intake should be wary of a higher risk of LSCC.

Glioblastoma multiforme (GBM) pathobiology is characterized by its significant induction of immunosuppression within the tumor microenvironment, predominantly mediated by immunosuppressive tumor-associated myeloid cells (TAMCs). Myeloid cells play a pivotal role in shaping the GBM microenvironment and influencing immune responses, with direct interactions with effector immune cells critically impacting these processes.

Our study investigates the role of the CXCR6/CXCL16 axis in T-cell myeloid interactions within GBM tissues. We examined the surface expression of CXCL16, revealing its limitation to TAMCs, while microglia release CXCL16 as a cytokine. The study explores how these distinct expression patterns affect T-cell engagement, focusing on the consequences for T-cell function within the tumor environment. Additionally, we assessed the significance of CXCR6 expression in T-cell activation and the initial migration to tumor tissues.

Our data demonstrates that CXCL16 surface expression on TAMCs results in predominant T-cell engagement with these cells, leading to impaired T-cell function within the tumor environment. Conversely, our findings highlight the essential role of CXCR6 expression in facilitating T-cell activation and initial migration to tumor tissues. The CXCL16-CXCR6 axis exhibits dualistic characteristics, facilitating the early stages of the T-cell immune response and promoting T-cell infiltration into tumors. However, once inside the tumor, this axis contributes to immunosuppression.

The dual nature of the CXCL16-CXCR6 axis underscores its potential as a therapeutic target in GBM. However, our results emphasize the importance of carefully considering the timing and context of intervention. While targeting this axis holds promise in combating GBM, the complex interplay between TAMCs, microglia, and T cells suggests that intervention strategies need to be tailored to optimize the balance between promoting antitumor immunity and preventing immunosuppression within the dynamic tumor microenvironment.

While tumor metastases represent the primary driver of cancer-related mortality, our understanding of the mechanisms that underlie metastatic initiation and progression remains incomplete. Recent work identified a novel tumor-macrophage hybrid cell population, generated through the fusion between neoplastic and immune cells. These hybrid cells are detected in primary tumor tissue, peripheral blood, and in metastatic sites. In-depth analyses of hybrid cell biology indicate that they can exploit phenotypic properties of both parental tumor and immune cells, in order to intravasate into circulation, evade the immune response, and seed tumors at distant sites. Thus, it has become increasingly evident that the development and dissemination of tumor-immune hybrid cells play an intricate and fundamental role in the metastatic cascade and can provide invaluable information regarding tumor characteristics and patient prognostication. In this chapter, we review the current understanding of this novel hybrid cell population, the specific hallmarks of cancer that these cells exploit to promote cancer progression and metastasis, and discuss exciting new frontiers that remain to be explored.

Autosomal dominant polycystic kidney disease (ADPKD) has cancer-like pathophysiology. In this study, we aimed to investigate the phenotype of peripheral blood (PB) T cell subsets and immune checkpoint inhibitor expression of ADPKD patients across different chronic kidney disease (CKD) stages. Seventy-two patients with ADPKD and twenty-three healthy controls were included in the study. The patients were grouped into five different CKD stages, according to glomerular filtration rate (GFR). PB mononuclear cells were isolated and T cell subsets and cytokine production were examined by flow cytometry. CRP levels, height-adjusted total kidney volume (htTKV), rate of hypertension (HT) differed significantly across different GFR stages in ADPKD. T cell phenotyping revealed significantly elevated CD3+ T cells, CD4+, CD8+, double-negative, and double-positive subsets and significantly elevated IFN-γ and TNF-α producing subsets of CD4+, CD8+ cells. The expression of checkpoint inhibitors CTLA-4, PD-1, and TIGIT by T cell subsets was also increased to various extent. Additionally, Treg cell numbers and suppressive markers CTLA-4, PD-1, and TIGIT were significantly elevated in ADPKD patients' PB. Treg CTLA4 expression and CD4CD8DP T cell frequency in patients with HT were significantly higher. Lastly, HT and increased htTKV and higher frequency of PD1+ CD8SP were found to be risk factors for rapid disease progression. Our data provide the first detailed analyses of checkpoint inhibitor expression by PB T cell subsets during stages of ADPKD, and that a higher frequency of PD1+ CD8SP cells is associated with rapid disease progression.

Colorectal cancer (CRC) ranks third in terms of incidence among all kinds of cancer. The main cause of death is metastasis. Recent studies have shown that the gut microbiota could facilitate cancer metastasis by promoting cancer cells proliferation, invasion, dissemination, and survival. Multiple mechanisms have been implicated, such as RNA-mediated targeting effects, activation of tumor signaling cascades, secretion of microbiota-derived functional substances, regulation of mRNA methylation, facilitated immune evasion, increased intravasation of cancer cells, and remodeling of tumor microenvironment (TME). The understanding of CRC metastasis was further deepened by the mechanisms mentioned above. In this review, the mechanisms by which the gut microbiota participates in the process of CRC metastasis were reviewed as followed based on recent studies.

Endoplasmic reticulum stress (ERS) is caused by the accumulation of intracellular misfolded or unfolded proteins and is associated with cancer development. In this study, pan-cancer analysis revealed complex genetic variations, including copy number variation, methylation, and somatic mutations for ERS-related genes (ERGs) in 33 kinds of cancer. Consensus clustering divided pancreatic cancer (PC) patients from TCGA and GEO databases into two ERS-related subtypes: ERGcluster A and B. Compared with ERGcluster A, ERGcluster B had a more active ERS state and worse prognosis. Subsequently, the ERS-related prognostic model was established to quantify the ERS score for a single sample. The patient with a low ERS score had remarkably longer survival times. ssGSEA and CIBERSORT algorithms revealed that activated B cells and CD8+ T cells had higher infiltration in the low ERS score group, but higher infiltration of activated CD4+ T cells, activated dendritic cells, macrophages, and neutrophils in the high ERS score group. Drug sensitivity analysis indicated the low ERS score group had a better response to gemcitabine, paclitaxel, 5-fluorouracil, oxaliplatin, and irinotecan. RT-qPCR validated that MET, MUC16, and KRT7 in the model had higher expression levels in pancreatic tumour tissues. Single-cell analysis further revealed that MET, MUC16, and KRT7 were mainly expressed in cancer cells in PC tumour microenvironment. In all, we first constructed the ERS-related molecular subtypes and prognostic model in PC. Our research highlighted the vital role of ERS in PC and contributed to further research on molecular mechanisms and novel therapeutic strategies for PC in the future.

Interleukin-6 (IL-6) is a crucial member of the cytokine network and plays a pivotal role in the pathogenesis of various diseases, including cancer. IL-6 receptor (IL-6R) blockade is widely employed as a therapeutic strategy; however, its efficacy in anticancer therapy remains ambiguous.

An inverse variance-weighted Mendelian randomization (MR) analysis was conducted to assess the causal effects exerted by IL-6R blockade in remediating cancer. Drug-targeted single-nucleotide polymorphisms (SNPs) were introduced within 300 kb of the IL-6R gene. An instrumental variable comprising 26 SNPs represented IL-6 signaling downregulation and C-reactive protein level reduction. Datasets pertaining to the 33 types of cancer investigated in this study were acquired from the FinnGen genome-wide association study.

The selected instrumental variable lowered fibrinogen levels, confirming its ability to mimic IL-6R blockade. IL-6R blockade exhibited therapeutic effects on five different cancer types documented in the FinnGen database (N = 334,364, including 76,781 cancer patients): bladder (odds ratios (OR) = 0.563), laryngeal (OR = 0.293), eye (OR = 0.098), gallbladder (OR = 0.059), and myeloid leukemia (OR = 0.442); however, it simultaneously elevated the risk of developing basal cell carcinoma (OR = 1.312) and melanoma (OR = 1.311). Sensitivity analyses did not alter the primary results.

Therefore, this study aimed to evaluate the potential and efficacy of SNP-based IL-6R blockade in treating cancer.

Immune checkpoint inhibitors (ICIs) have induced durable clinical responses in a subset of patients with colorectal cancer (CRC). However, the dis-satisfactory response rate and the lack of appropriate biomarkers for selecting suitable patients to be treated with ICIs pose a major challenge to current immunotherapies. Inflammation-related molecule A20 is closely related to cancer immune response, but the effect of A20 on "eat-me" signal and immunotherapy efficacy remains elusive. We found that A20 downregulation prominently improved the antitumor immune response and the efficacy of PD-1 inhibitor in CRC in vitro and in vivo. Higher A20 expression was associated with less infiltration of immune cells including CD3 (+), CD8 (+) T cells and macrophages in CRC tissues and also poorer prognosis. Gain- and loss-A20 functional studies proved that A20 could decrease the "eat-me" signal calreticulin (CRT) protein on cell membrane translocation via upregulating stanniocalcin 1 (STC1), binding to CRT and detaining in mitochondria. Mechanistically, A20 inhibited GSK3β phosphorylating STC1 at Thr86 to slow down the degradation of STC1 protein. Our findings reveal a new crosstalk between inflammatory molecule A20 and "eat-me" signal in CRC, which may represent a novel predictive biomarker for selecting CRC patients most likely to benefit from ICI therapy.

The advances in cancer research achieved in the last 50 years have been remarkable and have provided a deeper knowledge of this disease in many of its conceptual and biochemical aspects. From viewing a tumor as a 'simple' aggregate of mutant cells and focusing on detecting key cell changes leading to the tumorigenesis, the understanding of cancer has broadened to consider it as a complex organ interacting with its close and far surroundings through tumor and non-tumor cells, metabolic mechanisms, and immune processes. Metabolism and the immune system have been linked to tumorigenesis and malignancy progression along with cancer-specific genetic mutations. However, most technologies developed to overcome the barriers to earlier detection are focused solely on genetic information. The concept of cancer as a complex organ has led to research on other analytical techniques, with the quest of finding a more sensitive and cost-effective comprehensive approach. Furthermore, artificial intelligence has gained broader consensus in the oncology community as a powerful tool with the potential to revolutionize cancer diagnosis for physicians. We herein explore the relevance of the concept of cancer as a complex organ interacting with the bodily surroundings, and focus on promising emerging technologies seeking to diagnose cancer earlier, such as liquid biopsies. We highlight the importance of a comprehensive approach to encompass all the tumor and non-tumor derived information salient to earlier cancer detection.

An effective cancer therapy requires both killing cancer cells and targeting tumor-promoting pathways or cell populations within the tumor microenvironment (TME). We purposely search for molecules that are critical for multiple tumor-promoting cell types and identified nuclear receptor subfamily 4 group A member 1 (NR4A1) as one such molecule. NR4A1 has been shown to promote the aggressiveness of cancer cells and maintain the immune suppressive TME. Using genetic and pharmacological approaches, we establish NR4A1 as a valid therapeutic target for cancer therapy. Importantly, we have developed the first-of-its kind proteolysis-targeting chimera (PROTAC, named NR-V04) against NR4A1. NR-V04 effectively degrades NR4A1 within hours of treatment in vitro and sustains for at least 4 days in vivo, exhibiting long-lasting NR4A1-degradation in tumors and an excellent safety profile. NR-V04 leads to robust tumor inhibition and sometimes eradication of established melanoma tumors. At the mechanistic level, we have identified an unexpected novel mechanism via significant induction of tumor-infiltrating (TI) B cells as well as an inhibition of monocytic myeloid derived suppressor cells (m-MDSC), two clinically relevant immune cell populations in human melanomas. Overall, NR-V04-mediated NR4A1 degradation holds promise for enhancing anti-cancer immune responses and offers a new avenue for treating various types of cancer.