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As cancer is increasingly considered a metabolic disorder, it is postulated that serum metabolite profiling can be a viable approach for detecting the presence of cancer. By multiplexing mass spectrometry fingerprints from two independent nanostructured matrixes through machine learning for highly sensitive detection and high throughput analysis, we report a laser desorption/ionization (LDI) mass spectrometry-based liquid biopsy for pan-cancer screening and classification. The M ultiplexed N anomaterial- A ssisted L DI for C ancer I dentification (MNALCI) is applied in 1,183 individuals that include 233 healthy controls and 950 patients with liver, lung, pancreatic, colorectal, gastric, thyroid cancers from two independent cohorts. MNALCI demonstrates 93% sensitivity at 91% specificity for distinguishing cancers from healthy controls in the internal validation cohort, and 84% sensitivity at 84% specificity in the external validation cohort, with up to eight metabolite biomarkers identified. In addition, across those six different cancers, the overall accuracy for identifying the tumor tissue of origin is 92% in the internal validation cohort and 85% in the external validation cohort. The excellent accuracy and minimum sample consumption make the high throughput assay a promising solution for non-invasive cancer diagnosis. As cancer is increasingly considered a metabolic disorder, it is postulated that serum metabolite profiling can be a viable approach for detecting the presence of cancer. Here, the authors report a machine learning model using mass spectrometry-based liquid biopsy data for pan-cancer screening and classification.

When hepatocellular carcinoma (HCC) cells exhibit malignant biological behaviors, lipid metabolic reprogramming occurs concomitantly. Thus, identifying regulators of metabolic reprogramming offers new potential targets for therapy. In this study, we investigated the mechanisms by which Cyclic adenosine monophosphate-responsive element binding protein 3-like 2(CREB3L2) influences HCC progression and contributes to lenvatinib resistance through modulation of lipid metabolism. Up-regulated expression of CREB3L2 was observed in numerous HCC cohorts and associated with poor survival prognosis of patients. Furthermore, CREB3L2 could facilitate the proliferation and metastatic capacity of HCC cells both in vitro and in vivo. It was found that CREB3L2 influences the proliferation and metastasis of HCC cells by up-regulating sterol regulatory element binding protein 1 (SREBP1), a vital regulatory factor of lipid synthesis for fatty acid production. Additionally, CREB3L2 enhances SREBP1 protein expression and stability through increased acetylation mediated by histone acetyltransferase-1(HAT1). Importantly, targeting CREB3L2 in combination with lenvatinib significantly reduced lenvatinib resistance, inhibiting the progression of CREB3L2 high-expressing HCC tumors. These findings suggest that the CREB3L2/HAT1/SREBP1 regulatory axis drives lenvatinib resistance and HCC progression by impacting lipid metabolism. Targeting CREB3L2 alongside lenvatinib improves the efficacy of treating HCC.

The functional programs adopted by cancer cells and their impact on the tumor microenvironment are complex and remain unclear. Here, we identify three distinct single-cell archetypes (i.e. metabolism, stemness and inflammation) in hepatocellular carcinoma (HCC) cells, each exhibiting unique spatial distribution. Further analysis shows an immune-suppressive niche populated by metabolism archetype cancer cells and TREM2-positive tumor-associated macrophages (TREM2 + TAMs), which exacerbates immune exclusion and compromises patient outcomes. Mechanistically, we demonstrate that the upregulated squalene epoxidase (SQLE) expression in metabolism archetype cancer cells facilitates the generation of oxidized LDL (oxLDL). OxLDL induces TREM2 + TAM polarization through the TREM2-SYK-CEBPα axis, enabling these TAMs to promote cancer cell invasion, resistance to effector cytokines and CD8 + T cell dysfunction. Importantly, cancer cell-intrinsic SQLE and TREM2 + TAMs are associated with inferior immunotherapy response in human and mouse HCC. Our results highlight an oxLDL-mediated metabolic interplay between cancer cells and TREM2 + TAMs, offering a promising therapeutic avenue for HCC immunotherapies. Tumour cells can alter the function and metabolism of immune cells to reduce anti-tumour responses. Here the authors use single cell sequencing of HCC and show three tumour archetypes; metabolism, inflammation and stemness and the metabolism archetype are found in association with TREM + macrophages which restrict immune cell infiltration into the tumour microenvironment.

BackgroundRegulating T-cell metabolism is crucial for their anticancer activity. Therefore, understanding the function and metabolism of human tumor-infiltrating T cells is of broad interest and clinical importance.MethodsCD3+CD45+ T cells were sorted from adjacent area or tumor core of human hepatocellular carcinoma (HCC), then the clusters and heterogeneity of T cells were further interrogated by single-cell transcriptomic profiling. 118 surgical samples from patients with HCC were histologically examined for infiltration of CD8+ T cells in tumor and adjacent tissue.ResultsSingle-cell transcriptomic profiling indicated that several exhausted T-cell (Tex) populations differentially coexisted in the tumor and adjacent tissue. CD137 identifies and enriches Tex with superior effector functions and proliferation capacity. Furthermore, enhanced fatty acid-binding protein 5 (FABP5) expression along with increased mitochondrial oxidative metabolism were evident in these CD137-enriched Tex. Inhibiting FABP5 expression and mitochondrial fatty acid oxidation impaired the anti-apoptosis and proliferation of CD137-enriched Tex. These observations have been verified by generating CD137 CART. Immunohistochemistry staining on the tissue microarray of 118 patients with HCC showed intra-tumoral FABP5 high CD8+ T-cell infiltration was linked to overall and recurrence-free survival.ConclusionsThe tumor microenvironment can impose metabolic restrictions on T-cell function. CD137, a costimulatory molecule highly expressed on some Tex, uses exogenous fatty acids and oxidative metabolism to mediate antitumor immunity. The immunometabolic marker FABP5 should be investigated in larger, longitudinal studies to determine their potential as prognostic biomarkers for HCC.

Although multiple targeted treatments have appeared, hepatocellular carcinoma (HCC) is still one of the most common causes of cancer-related deaths. The immunosuppressive tumor microenvironment (TME) is a critical factor in the oncogenesis and progression of HCC. The emerging scRNA-seq makes it possible to explore the TME at a high resolution. This study was designed to reveal the immune-metabolic crosstalk between immune cells in HCC and provide novel strategies to regulate immunosuppressive TME. In this study, we performed scRNA-seq on paired tumor and peri-tumor tissues of HCC. The composition and differentiation trajectory of the immune populations in TME were portrayed. Cellphone DB was utilized to calculate interactions between the identified clusters. Besides, flow cytometry, RT-PCR and seahorse experiments were implemented to explore potential metabolic and epigenetic mechanisms of the inter-cellular interaction. A total of 19 immune cell clusters were identified and 7 were found closely related to HCC prognosis. Besides, differentiation trajectories of T cells were also presented. Moreover, a new population, CD3+C1q+ tumor-associated macrophages (TAM) were identified and found significantly interacted with CD8+ CCL4+T cells. Compared to the peri-tumor tissue, their interaction was attenuated in tumor. Additionally, the dynamic presence of this newly found cluster was also verified in the peripheral blood of patients with sepsis. Furthermore, we found that CD3+C1q+TAM affected T cell immunity through C1q signaling-induced metabolic and epigenetic reprogramming, thereby potentially affecting tumor prognosis. Our study revealed the interaction between CD3+C1q+TAM and CD8+ CCL4+T cells and may provide implications for tackling the immunosuppressive TME in HCC.

Intrahepatic cholangiocarcinoma (ICC) remains a highly heterogeneous disease with poor prognosis. Tumor‐infiltrating lymphocytes were predictive in various cancers, but their prognostic value in ICC is less clear. A total of 168 ICC patients who had received liver resection were enrolled and assigned to the derivation cohort. Sixteen immune markers in tumor and peritumor regions were examined by immunohistochemistry. A least absolute shrinkage and selection operator model was used to identify prognostic markers and to establish an immune signature for ICC (ISICC). An ISICC‐applied prediction model was built and validated in another independent dataset. Five immune features, including CD3peritumor (P), CD57P, CD45RAP, CD66bintratumoral (T) and PD‐L1P, were identified and integrated into an individualized ISICC for each patient. Seven prognostic predictors, including total bilirubin, tumor numbers, CEA, CA19‐9, GGT, HBsAg and ISICC, were integrated into the final model. The C‐index of the ISICC‐applied prediction model was 0.719 (95% CI, 0.660‐0.777) in the derivation cohort and 0.667 (95% CI, 0.581‐0.732) in the validation cohort. Compared with the conventional staging systems, the new model presented better homogeneity and a lower Akaike information criteria value in ICC. The ISICC‐applied prediction model may provide a better prediction performance for the overall survival of patients with resectable ICC in clinical practice. Using tissue microarray, we examined the density of 16 immune biomarkers in 280 ICC patients who underwent hepatectomy, and established a novel ISICC‐based prediction model (IPM) to predict patients’ overall survival with bilirubin, tumor numbers, CEA, CA19‐9, γ‐glutamyl transferase (GGT), HBsAg and ISICC. The new model may provide a better prediction performance for the overall survival of patients with resectable ICC in clinical practice.

Mixed lineage kinase domain-like (MLKL) is widely accepted as an executioner of necroptosis, in which MLKL mediates necroptotic signaling and triggers cell death in a receptor-interacting protein kinase 3 (RIPK3)-dependent manner. Recently, it is increasingly noted that RIPK3 is intrinsically silenced in hepatocytes, raising a question about the role of MLKL in hepatocellular carcinoma (HCC). This study reports a previously unrecognized role of MLKL in regulating parthanatos, a programmed cell death distinct from necroptosis. In HCC cells with intrinsic RIPK3 deficiency, knockout of MLKL impedes the orthotopic tumor growth, activates the anti-tumor immune response and enhances the therapeutic effect of immune checkpoint blockade in syngeneic HCC tumor models. Mechanistically, MLKL is required for maintaining the endoplasmic reticulum (ER)-mitochondrial Mg2+ dynamics in HCC cells. MLKL deficiency restricts ER Mg2+ release and mitochondrial Mg2+ uptake, leading to ER dysfunction and mitochondrial oxidative stress, which together confer increased susceptibility to metabolic stress-induced parthanatos. Importantly, pharmacological inhibition of poly(ADP-ribose) polymerase to block parthanatos restores the tumor growth and immune evasion in MLKL-knockout HCC tumors. Together, our data demonstrate a new RIPK3-independent role of MLKL in regulating parthanatos and highlight the role of MLKL in facilitating immune evasion in HCC.

The 5-methylcytosine (m5C) post-transcriptional modification has been linked with the development and progression of a variety of cancers. However, its specific functions and their underlying mechanisms are poorly understood in hepatocellular carcinoma (HCC). The present study showed abnormally increased levels of m5C modifications in HCC that were positively correlated with both HCC progression and worse patient prognosis. Landscape profiling of metabolic characteristics showed dysregulation of pyrimidine metabolism mediated by DNA methyltransferases 1 (DNMT1), and cyclin-dependent kinase 1 (CDK1) was identified as a downstream effector upregulated by DNMT1 in an m5C-dependent manner, with CDK1 promoting pyrimidine metabolism. Knockdown of DNMT1 or CDK1 was found to reduce the proliferation, invasion, and migration of HCC cells in vitro. Moreover, pharmacological targeting of the DNMT1/CDK1/pyrimidine metabolism axis with specific inhibitors effectively suppressed tumor progression in HCC model mice. These findings demonstrated the landscape profiles of m5C-related metabolic features in HCC, showing stabilization of CDK1 mRNA by DNMT1-mediated m5C modification, resulting in the promotion of pyrimidine metabolism, a crucial feature of HCC progression. These insights highlight the therapeutic potential of targeting the DNMT1/CDK1/pyrimidine metabolism axis as a strategy for combating HCC.

Background SQSTM1/p62 is a selective autophagy receptor that regulates multiple signaling pathways participating in the initiation and progression of tumors. Metastasis is still the main cause for intrahepatic cholangiocarcinoma (ICC)‐associated mortality. Hence, this study aimed to explore the mechanism of p62 promoting the progression of ICC. Methods Western blotting and immunohistochemical analyses were conducted to detect the expression level of protein p62 in ICC tissues and its correlation with prognosis. Subsequently, the loss‐of‐function experiments in vitro and in vivo were performed to define the role of p62 in ICC cell proliferation, invasion, and metastasis. Then, the effect of p62 knockdown on mitochondrial function and mitophagy was evaluated by measuring the oxygen consumption rate, and using immunofluorescence and western blotting analyses. Results The expression of p62 was significantly upregulated in ICC specimens compared with normal tissues. We further illustrated that p62 expression positively correlated with lymph node metastasis and poor prognosis. The loss‐of‐function assays revealed that p62 not only promoted ICC cell proliferation, migration, and invasive capacities in vitro, but also induced lung metastasis in the xenograft mouse model. Mechanistically, high expression of p62‐induced epithelial–mesenchymal transition (EMT) with the upregulation of Snail, vimentin, N‐cadherin, and downregulation of E‐cadherin. Moreover, the autophagy‐dependent function of p62 might play a vital role in maintaining the mitochondrial function of ICC by mitophagy which might further promote EMT. Conclusion These data provided new evidence for the mechanism by which abundant p62 expression promoted ICC progression, suggesting a promising therapeutic target for antimetastatic strategies in patients with ICC. SQSTM1/p62 not only promoted ICC cells proliferation, migration and invasive capacity in vitro, but also induced lymph‐node metastasis in vivo by inducing epithelial‐mesenchymal transition process. And the autophagy‐dependent function of p62 may play a vital role in EMT of ICC by mitophagy.

Background Intrahepatic cholangiocarcinoma (iCCA) is a highly heterogeneous and lethal hepatobiliary tumor with few therapeutic strategies. The metabolic reprogramming of tumor cells plays an essential role in the development of tumors, while the metabolic molecular classification of iCCA is largely unknown. Here, we performed an integrated multiomics analysis and metabolic classification to depict differences in metabolic characteristics of iCCA patients, hoping to provide a novel perspective to understand and treat iCCA. Methods We performed integrated multiomics analysis in 116 iCCA samples, including whole‐exome sequencing, bulk RNA‐sequencing and proteome analysis. Based on the non‐negative matrix factorization method and the protein abundance of metabolic genes in human genome‐scale metabolic models, the metabolic subtype of iCCA was determined. Survival and prognostic gene analyses were used to compare overall survival (OS) differences between metabolic subtypes. Cell proliferation analysis, 5‐ethynyl‐2'‐deoxyuridine (EdU) assay, colony formation assay, RNA‐sequencing and Western blotting were performed to investigate the molecular mechanisms of diacylglycerol kinase α (DGKA) in iCCA cells. Results Three metabolic subtypes (S1‐S3) with subtype‐specific biomarkers of iCCA were identified. These metabolic subtypes presented with distinct prognoses, metabolic features, immune microenvironments, and genetic alterations. The S2 subtype with the worst survival showed the activation of some special metabolic processes, immune‐suppressed microenvironment and Kirsten rat sarcoma viral oncogene homolog (KRAS)/AT‐rich interactive domain 1A (ARID1A) mutations. Among the S2 subtype‐specific upregulated proteins, DGKA was further identified as a potential drug target for iCCA, which promoted cell proliferation by enhancing phosphatidic acid (PA) metabolism and activating mitogen‐activated protein kinase (MAPK) signaling. Conclusion Via multiomics analyses, we identified three metabolic subtypes of iCCA, revealing that the S2 subtype exhibited the poorest survival outcomes. We further identified DGKA as a potential target for the S2 subtype.