A drastic difference exists between the 5-year survival rates of colorectal cancer patients with localized cancer and distal organ metastasis. The liver is the most favorable organ for cancer metastases from the colorectum. Beyond the liver-colon anatomic relationship, emerging evidence highlights the impact of liver immune microenvironment on colorectal liver metastasis. Prior to cancer cell dissemination, hepatocytes secrete multiple factors to recruit or activate immune cells and stromal cells in the liver to form a favorable premetastatic niche. The liver-resident cells including Kupffer cells, hepatic stellate cells, and liver-sinusoidal endothelial cells are co-opted by the recruited cells, such as myeloid-derived suppressor cells and tumor-associated macrophages, to establish an immunosuppressive liver microenvironment suitable for tumor cell colonization and outgrowth. Current treatments including radical surgery, systemic therapy, and localized therapy have only achieved good clinical outcomes in a minority of colorectal cancer patients with liver metastasis, which is further hampered by high recurrence rate. Better understanding of the mechanisms governing the metastasis-prone liver immune microenvironment should open new immuno-oncology avenues for liver metastasis intervention.

Background: Cuproptosis is a newly discovered form of programmed cell death, which is characterized by accumulation of intra-cellular copper ion leading to the aggregation of lipoproteins and destabilization of Fe-S cluster proteins in mitochondrial metabolism, thereby affecting the prognosis of patients with cancer. However, the role of cuproptosis-related genes (CRGs) in hepatocellular carcinoma (HCC) remains elusive.Methods: Mutation signature, copy number variation and the expression of 10 CRGs were assessed in HCC from TCGA-LIHC dataset. ICGC-LIRI-JP dataset was used as further validation cohort. The least absolute shrinkage and selection operator (LASSO) was used to construct the prognostic model. Kaplan Meier curves, time-ROC curves, nomogram, univariate and multivariate Cox regression were utilized to evaluate the predictive efficacy of CRGs-score. Immune infiltration was analyzed by CIBERSOFT, ssGSEA algorithm, and TIMER database. The expression of prognostic CRGs was validated by qPCR both in-vitro and in-vivo. Drug sensitivity analysis was performed by pRRophetic.Results: All of the CRGs were differentially expressed in HCC and 5 out of them (CDKN2A, DLAT, GLS, LIPT1, MTF1) correlated with patient survival. These signature genes were selected by LASSO analysis to establish a prognosis model to stratify HCC patients into high and low CRGs-score subgroups. High CRGs-score was associated with a worse prognosis. Subsequently, univariate and multivariate Cox regression verified that CRGs-score was an independent cancer risk factor that correlated with clinical factors including stage and grade. Nomogram integrating the CRGs-score and clinical risk factors performed well to predict patient survival. Immune infiltration analysis further revealed that the expression of immune checkpoint genes was significantly enhanced in high CRGs-score group, especially PD-1 and PD-L1. An independent validation cohort (ICGC) confirmed that CRGs-score as a stable and universally applicable indicator in predicting HCC patient survival. Concordantly, the expression of five confirmed signature genes were also differentially expressed in human HCC cell lines and mouse HCC model. In addition, we also analyzed the sensitivity of 10 clinical targeted therapies between high and low CRGs-score groups.Conclusion: This study elucidated the role of dysregulated CRGs in HCC cohort, with validation with in-vitro and in-vivo models. The CRGs-score might be applied as a novel prognostic factor in HCC.

Introduction: Schizophrenia (SCZ) is a severe psychiatric disorder whose pathophysiology remains elusive. Recent investigations have underscored the significance of systemic inflammation, particularly the impact of circulating inflammatory proteins, in SCZ.Methods: This study explores the potential causal association between certain inflammatory proteins and SCZ. Bidirectional Mendelian randomization (MR) analyses were conducted utilizing data from expansive genome-wide association studies (GWAS). Data regarding circulating inflammatory proteins were sourced from the GWAS Catalog database, encompassing 91 inflammatory cytokines. SCZ-related data were derived from the Finngen database, incorporating 47,696 cases and 359,290 controls. Analytical methods such as inverse variance weighted, MR-Egger, weighted median, simple mode, and weighted mode were employed to evaluate the association between inflammatory cytokines and SCZ. Sensitivity analyses were also performed to affirm the robustness of the results.Results: Following FDR adjustment, significant associations were observed between levels of inflammatory cytokines, including Fibroblast Growth Factor 5 (OR = 1.140, 95%CI = 1.045, 1.243, p = 0.003, FDR=0.015), C-C Motif Chemokine 4 (OR = 0.888, 95%CI = 0.816, 0.967, p = 0.006, FDR = 0.015), C-X-C Motif Chemokine 1 (OR = 0.833, 95%CI = 0.721, 0.962, p = 0.013, FDR = 0.064), and C-X-C Motif Chemokine 5 (OR = 0.870, 95%CI = 0.778, 0.973, p = 0.015, FDR = 0.074), and the risk of SCZ.Conclusion: Our results from MR analysis suggest a potential causal link between circulating inflammatory cytokines and SCZ, thereby enriching our understanding of the interactions between inflammation and SCZ. Furthermore, these insights provide a valuable foundation for devising therapeutic strategies targeting inflammation.

The liver microenvironment is essential to immune surveillance and liver cancer progression. Here, the aim is to identify the role of METTL5, the 18S rRNA m ⁶ A methyltransferase, in regulating the liver immune microenvironment to promote cancer progression. Liver‐specific Mettl5 knockout (cKO) in mice exhibits increased immune cell infiltration, especially CD3 ⁺ and CD4 ⁺ T cells. Loss of Mettl5 inhibits intrahepatic cholangiocarcinoma (ICC) progression. By scRNA‐seq analysis, it is found that ICC from both cKO mice and human METTL5 low expression group correlates with increased CD8 ⁺ T cells but decreased macrophages, which is associated with better survival. Adoptive transfer of macrophages significantly promotes ICC progression. scRNA‐seq and scTCR‐seq analysis show that cKO mice exhibit reduced immunosuppressive Ms4a7 ⁺ C1qa ⁺ tumor‐associated macrophages (TAMs) but increased intratumoral IFN‐γ ⁺ CD8 ⁺ T cell infiltration and expansion. Mechanistically, METTL5‐mediated 18S rRNA m ⁶ A modification downregulates the mRNA translation of CXCL16 to exclude CD8 ⁺ T cells. Knockout of Mettl5 significantly increases CD8 ⁺ T cell infiltration in vivo. Combined METTL5 targeting using lipid nanoparticle‐encapsulated siRNA and PD‐1 blockade provokes anti‐tumor immunity to eradicate ICC tumors. Additionally, METTL5 ^Low human ICC correlates with responsiveness to immunotherapy. The study highlights the strong immuno‐evasive ability of METTL5 as a promising therapeutic target in ICC.