Objective: Anti-PD-1 therapy resistance remains a critical barrier in non-small cell lung cancer (NSCLC) management, and the underlying mechanisms are incompletely defined.

Methods: We generated CD155-knockout (KO) NSCLC cell lines using the CRISPR-Cas9 system and performed systematic multi-omics analyses, including single-cell RNA-seq, bulk RNA-seq, proteomics, and metabolomics. The key molecular mechanisms were further validated by immunohistochemistry (IHC), western blotting, and chromatin immunoprecipitation (ChIP). Functional assays assessed cell proliferation, migration, and metabolic phenotypes, while the therapeutic efficacy was assessed in vivo using AAV9_shCD155.

Results: Single-cell sequencing revealed aberrantly high CD155 expression in NSCLC patients with poor response to anti-PD-1 therapy. High CD155 expression in NSCLC tissues correlated with unfavourable prognosis. ETS1 was identified as a direct transcriptional driver of CD155. Multi-omics analysis and functional assays demonstrated that CD155 upregulates the expression of key glycolytic proteins (GLUT1, GLUT3, LDHB) by activating the PI3K/AKT/HIF-1α signalling axis, thereby driving glycolytic metabolism, proliferation, and migration of tumour cells. CD155 knockout significantly suppressed these malignant phenotypes. In xenograft mouse models, monotherapy with AAV9_shCD155 effectively inhibited tumour growth and postoperative recurrence. More importantly, in humanised mouse models, combining AAV9_shCD155 with pembrolizumab produced synergistic anti-tumour effects, more significantly suppressing tumour growth and promoting immune cell infiltration into the tumour microenvironment.

Conclusion: CD155 mediates anti-PD-1 resistance by activating PI3K/AKT/HIF-1α-driven glycolytic reprogramming. Targeting CD155 combined with anti-PD-1 overcomes resistance, supporting a dual-target therapeutic strategy.

Background: Non-small cell lung cancer (NSCLC) remains a leading cause of global cancer mortality. Increasing evidence implicates aberrant cholesterol metabolic reprogramming as a key facilitator of tumour malignancy; however, the mechanistic connections between lipoprotein metabolism and NSCLC pathogenesis remain elusive. Here, we investigate the unrecognised oncogenic role of cholesteryl ester transfer protein (CETP), a central lipid exchange mediator.

Methods: Serum lipid profiles from 151 NSCLC patients were analysed, and CETP mRNA expression level was evaluated in normal lung (n = 47) and NSCLC tissue (n = 54) and paired NSCLC tissue microarrays (n = 113). Integrated ChIP-seq/RNA-seq analyses, ChIP–qPCR, dual-luciferase reporter and ubiquitination assays were performed to investigate CTBP1-mediated CETP transcription. Functional studies in NSCLC cells, xenograft models and eight patient-derived organoids evaluated the role of the CTBP1–CETP axis in lipid remodelling, ferroptosis and the therapeutic efficacy of obicetrapib alone or combined with RSL3.

Results: CETP was significantly up-regulated in NSCLC tissues and predicted poor overall survival in both LUAD (HR = 1.46, 95% CI 1.13–1.87, p = .0033) and LUSC (HR = 1.51, 95% CI 1.12–2.01, p = .0067). CTBP1 activated CETP transcription, and CTBP1 ubiquitination further enhanced its transcriptional activity. The CTBP1–CETP axis promoted ferroptosis resistance by lipid accumulation. Obicetrapib phenocopied CETP depletion and synergised with RSL3 to inhibit tumour growth in NSCLC cells, xenografts and patient-derived organoids.

Conclusions: Our study delineates a novel CTBP1–CETP–lipid droplet–MAPK signalling cascade that couples metabolic rewiring with ferroptosis evasion. These insights establish the CTBP1–CETP axis as a critical cell fate determinant, positioning pharmacological CETP inhibition (e.g., obicetrapib) as a translatable therapeutic vulnerability in lipid-dependent, ferroptosis-resistant NSCLC.

Background: Resistance to immune checkpoint blockade substantially limits its clinical efficacy in head and neck squamous cell carcinoma(HNSCC). ZC3H13 is a component of the N6-methyladenosine writer complex, but its roles in HNSCC progression and response to anti-programmed cell death protein 1(anti-PD-1) therapy remain unclear.

Methods: The expression and clinical relevance of ZC3H13 were evaluated using clinical cohorts and publicly available transcriptomic datasets. Gain- and loss-of-function experiments were performed to determine the effects of ZC3H13 on the malignant phenotypes of HNSCC cells. An epithelial-specific ZC3H13 conditional knockout mouse model of 4-nitroquinoline-1-oxide-induced oral tumorigenesis was used to assess tumor development and responsiveness to anti-PD-1 therapy. N6-methyladenosine modification, RNA stability and functional rescue assays were conducted to investigate the underlying molecular mechanism.

Results: ZC3H13 was upregulated in HNSCC and was associated with poor prognosis and a limited response to anti-PD-1 treatment. ZC3H13 promoted the proliferation and invasion of HNSCC cells, whereas epithelial-specific ablation of ZC3H13 suppressed oral tumorigenesis and enhanced the therapeutic efficacy of anti-PD-1 treatment. Mechanistically, ZC3H13 regulated the N6-methyladenosine modification of cyclin D1(CCND1) mRNA and promoted its IGF2BP1-dependent stabilization, thereby contributing to malignant tumor phenotypes and alterations in immunosuppressvie features.

Conclusions: The ZC3H13/IGF2BP1/CCND1 regulatory axis contributes to HNSCC progression and resistance to anti-PD-1 therapy. These findings identify ZC3H13 as a potential therapeutic target for improving the efficacy of anti-PD-1 treatment in HNSCC.

Background: Duchenne muscular dystrophy (DMD)-associated cardiomyopathy is a leading causes of premature death, yet treatment options remain limited. In this study, we developed the easily accessible engineered exosomes for treatment of DMD-associated cardiomyopathy and explored the underlying mechanisms in DmdΔ4 mice, a model harboring hot spot mutation in the dystrophin gene.

Methods: DmdΔ4 mice and their cardiomyopathy phenotype were confirmed by Sanger sequencing, pathological staining, flow cytometry, immunoblotting, single-cell sequencing and echocardiographic analysis. Engineered exosomes, exosomes- cardiac homing peptide (Exo-CHP), were synthesised and characterised by click chemistry and miRNA sequence, separately. The targeted ability and the therapeutic effects of Exo-CHP were studied in vitro and in vivo. Primary cardiomyocytes were used to study the underlying mechanism of Exo-CHP.

Results: DmdΔ4 mice showed an obvious cardiomyopathy-associated phenotype. Exo-CHP can target myocardium and mitigate pathological progression of cardiomyopathy in DmdΔ4 mice. The therapeutic effects of intravenously delivered Exo-CHP significantly reduced myocardial inflammation, fibrosis and improved the mice's cardiac function. The rescue effects were mediated through the regulation of gene expression at the transcriptomic level, prevention of dystrophin protein complex degradation, and inhibition of intracellular calcium influx and calpain protease activity. The miR-21 knockdown Exo-CHP can counteract the protective effects of Exo-CHP on the calcium content and membrane integrity of primary DmdΔ4-derived cardiomyocytes.

Conclusions: Our study demonstrated the feasibility, efficacy and the possible mechanism of mesenchymal stromal cell-derived engineered exosomes, positioning them as a potential cell-free intervention for DMD-associated cardiomyopathy.

Background: Disruption of host–microbiota homeostasis is a fundamental hallmark of inflammatory bowel disease (IBD) pathogenesis. Host epigenetic modifications and corresponding alterations in gene expression levels can impact the composition of gut microbes. SET domain containing 2 (SETD2) is a critical epigenetic regulator with established tumor-suppressive roles, but its function in intestinal microbial ecology and colitis progression remains unexplored. We aimed to investigate the specific role of SETD2 in maintaining gut microbial homeostasis and modulating colitis progression.

Methods: RNA sequencing (RNA-seq), assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and cleavage under targets and tagmentation sequencing (CUT&Tag-seq) were conducted on colonic epithelial cells from intestinal epithelial cell-specific SETD2 knockout (Setd2^vil-ko) mice to identify key mediators contributing to colitis development. Faecal samples underwent 16S rRNA sequencing and non-targeted metabolomics analysis to characterise microbial dysbiosis and metabolic perturbations. Molecular experiments and faecal microbiome transplantation experiment were conducted to explore and validate the role of SETD2 in colitis development.

Results: SETD2 deficiency induced overproduction of Reg3 lectins and disrupted gut microbiota composition. Beneficial commensal bacteria were depleted and dysregulated metabolites were accumulated in Setd2^vil-ko mice. Supplementation with healthy-like gut microbiota significantly ameliorated the exacerbated colitis induced by SETD2 deficiency.

Conclusions: Our findings uncover a previously unrecognised role for SETD2 in maintaining microbial homeostasis, offering new mechanistic insights into how epigenetic regulation preserves intestinal homeostasis and suggesting novel therapeutic avenues for IBD.

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies and is characterised by aggressive biological behaviour, marked therapeutic resistance and a dense desmoplastic tumour microenvironment. Integrin α5β1, the principal fibronectin receptor, has emerged as an important mediator of tumour-stroma interactions through its roles in cell adhesion, mechanotransduction, migration, survival and extracellular matrix (ECM) remodelling.

Main body: Increasing evidence indicates that integrin alpha 5 (ITGA5)/integrin α5β1 is upregulated in PDAC cells and stromal compartments and is associated with invasion, fibrosis, therapeutic resistance and poor prognosis. Hypoxia, a defining feature of PDAC, may further enhance α5β1-related signalling by promoting stromal activation and ECM remodelling. This review summarises the structural and signalling features of integrin α5β1, its role in hypoxia-related interactions between tumour cells and the stroma, its contribution to therapeutic resistance in PDAC, and current therapeutic strategies targeting this integrin.

Conclusion: Integrin α5β1 is a biologically relevant therapeutic target for modulating the fibrotic stroma and overcoming treatment resistance in PDAC, and it may also be implicated in tumorstroma crosstalk within the hypoxic microenvironment. Successful clinical translation of α5β1-targeted strategies will likely require further mechanistic investigation, biomarker-guided patient selection, and rational combination approaches to address pathway redundancy and the limited efficacy of monotherapy.

Background: Adipose tissue remodelling, encompassing white adipose tissue (WAT) browning alongside brown adipose tissue (BAT) activation, holds promise for combating obesity, yet the endogenous chemokine receptors that restrain this plasticity remain ill-defined. Here, we uncover that C‒C chemokine receptor 1 (CCR1) restrains adipocyte remodelling and energy expenditure.

Methods: A high-fat diet (HFD) was provided to systemic and adipocyte-specific Ccr1 knockout mice. The CCR1-selective antagonist BX471 was administered to HFD-fed wild-type (WT) mice as a preventive regimen. Energy expenditure was assessed via indirect calorimetry; BAT thermogenic activity and WAT beiging were quantified through histology and gene expressin analyses. Adipose tissue macrophage homeostasis was analysed via flow cytometry. Peritoneal macrophages were differentiated into either the M1 or M2 state, and conditioned media were applied to the adipocytes.

Results: In HFD-fed mice, Ccr1 ablation conferred resistance to obesity and insulin resistance, coupled with enhanced WAT browning, augmented BAT thermogenesis and elevated energy expenditure. These metabolic benefits were associated with a shift towards M2 macrophage polarisation and reduced adipose tissue inflammation. Adipocyte-specific Ccr1 knockout recapitulated these phenotypes. BX471 administration in WT mice phenocopied the metabolic effects of Ccr1 deficiency under HFD conditions. Mechanistically, in vitro experiments suggested that Ccr1 loss suppressed Gαi-dependent signalling, leading to increased intracellular cyclic adenosine monophosphate (cAMP) and subsequent protein kinase A/cAMP-response element-binding protein 1 (PKA/CREB) activation, thereby promoting thermogenic gene expression in adipocytes. In addition, conditioned media from M2-polarised macrophages enhanced thermogenic gene expression in adipocytes, and this effect was further potentiated in Ccr1-deficient adipocytes.

Conclusion: CCR1 regulates adipose tissue remodelling and systemic energy expenditure, at least in part, through cAMP/PKA/CREB signalling and macrophage homeostasis. Pharmacological inhibition of CCR1 attenuates obesity development, suggesting a potential preventive strategy.

Background: Colorectal cancer (CRC) is a leading cause of cancer-related death and is associated with high recurrence rates. Solute carrier family 7 member 5 (SLC7A5), a core transporter that facilitates the transmembrane movement of tryptophan, plays a role in various cancers. However, whether and how SLC7A5 promotes colorectal liver metastasis (CRLM) through tryptophan metabolism reprogramming and immune remodelling remain unexplored.

Methods: We integrated public datasets and clinical specimens to analyse SLC7A5 expression and prognosis, and validated its role in proliferation and metastasis using in vitro assays and in vivo models. Targeted metabolomics and isotope tracing identified kynurenine (Kyn) and xanthurenic acid (XANA) as downstream metabolites of SLC7A5. Single-cell RNA sequencing (scRNA-seq) and conditioned medium experiments were used to assess the impact of SLC7A5 on the tumour immune microenvironment (TIME).

Results: SLC7A5 expression increases sequentially in normal tissue, primary tumours and liver metastases, and higher SLC7A5 levels are associated with worse prognosis. SLC7A5 facilitates CRC cell growth, metastasis and epithelial‒mesenchymal transition (EMT) by promoting the production of Kyn and XANA and subsequent activation of the aryl hydrocarbon receptor (AhR). scRNA-seq analysis and conditioned medium experiments demonstrated that SLC7A5 knockdown reprograms the TIME by driving macrophages towards an antigen-presenting phenotype, alleviating CD8⁺ T-cell exhaustion, polarising CD4⁺ T cells towards Th1/Th17 subsets and triggering antigen-driven immunoglobulin G (IgG)-secreting B-cell clonal expansion, effects that were reversed by exogenous Kyn/XANA supplementation. Moreover, combination therapy with the SLC7A5 inhibitor JPH203 and anti-programmed cell death protein 1 (PD-1) antibody produced synergistic tumour growth inhibition and heightened antitumour immune responses.

Conclusions: Collectively, our findings reveal that SLC7A5 drives CRLM through tryptophan/Kyn/XANA–AhR signalling and concomitant remodelling of the TIME, positioning SLC7A5 as a promising target for combination therapy with anti-PD-1 in CRLM.

Septic cardiomyopathy is characterized by acute cardiac dysfunction, while sustained inflammatory and extracellular matrix remodeling may contribute to subsequent myocardial fibrosis and impaired cardiac recovery. A disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4) has been linked to fibrotic remodelling, but its role in septic cardiac injury remains unclear. Here, we show that Adamts4 is upregulated in LPS-induced septic mouse hearts and is predominantly induced in cardiac fibroblasts. Using three fibroblast-lineage Adamts4 knockout models, we demonstrate that Adamts4 deletion attenuates LPS-induced cardiac dysfunction, inflammation and fibrosis, whereas Tcf21-lineage fibroblast Adamts4 overexpression aggravates these changes. Mechanistically, ADAMTS4 interacts with thrombospondin-1 (TSP1) and promotes its catalytic activity-dependent proteolytic processing. The 236–246 amino acid region of TSP1 is required for fragment generation and fibroblast activation. TSP1 processing further activates TGF-β/Smad and NF-κB signalling, promoting myofibroblast activation and extracellular matrix deposition. These findings identify ADAMTS4 as a fibroblast-centred driver of septic cardiac fibrosis and suggest that targeting the ADAMTS4-TSP1 axis may offer therapeutic potential for septic cardiomyopathy.

Background: Hepatocellular carcinoma (HCC) is characterized by pronounced metabolic reprogramming and is frequently accompanied by the development of an immunosuppressive microenvironment. However, the key molecular mediators linking tumour metabolic dysregulation to immune microenvironment remodelling remain insufficiently defined. This study aimed to identify critical metabolic genes in HCC and to investigate their roles in lipid metabolic reprogramming and immunosuppression.

Methods: A deep autoencoder was used to extract latent metabolic features from HCC and identify TALDO1 as a key candidate gene. The expression pattern and prognostic significance of TALDO1 were evaluated across multiple independent cohorts and further validated in clinical specimens. Multi-omics analyses combined with experimental validation were then used to elucidate the role of TALDO1 in lipid metabolic reprogramming and its effects on immune microenvironment remodelling in HCC.

Results: TALDO1 was identified as a key metabolic gene associated with HCC progression and was consistently upregulated across multiple clinical cohorts. Mechanistically, TALDO1 promoted lipogenesis and lipid accumulation in HCC cells by suppressing AMPK activation and sustaining SREBP1 maturation. TALDO1 silencing also reduced the secretion of several fatty acids and lipid mediators. Multi-omics analyses together with multiplex immunofluorescence validation showed that high TALDO1 expression was associated with an immunosuppressive microenvironment in HCC. Coculture experiments further demonstrated that TALDO1 silencing attenuated the ability of HCC cells to induce M2-like macrophage polarization and promote phenotypes associated with T-cell exhaustion. In vivo, TALDO1 loss was accompanied by reduced immunosuppressive cell infiltration, enhanced effector T-cell activity, and impaired tumour growth. Consistently, TALDO1 silencing also markedly suppressed tumour growth in patient-derived xenograft models.

Conclusions: TALDO1 promotes lipid metabolic reprogramming in HCC and participates in the formation of an immunosuppressive microenvironment. These findings suggest that TALDO1 may serve as a key molecule linking metabolic abnormalities to immune microenvironment remodelling and may have potential therapeutic significance.

Background: Gastric cancer (GC) remains a major health burden because of late-stage diagnosis and resistance to systemic therapy.

Main body: In GC, the Warburg effect is driven by interconnected hypoxia and oncogenic signalling, non-coding RNA networks and transcriptional and epigenetic rewiring. These regulators converge on glucose transport and core glycolytic enzymes, including HK2, PFKFB3, PKM2 and LDHA. The resulting increase in aerobic glycolysis, pyruvate-to-lactate conversion and lactate export supports biosynthesis, redox homeostasis and survival under metabolic stress. Beyond its bioenergetic role, lactate acts as a signalling metabolite that acidifies and remodels the tumour microenvironment. It impairs CD8-positive T and natural killer cells function, promotes regulatory T cells accumulation and M2 macrophages polarisation, activates stromal cells and facilitates epithelial–mesenchymal transition and immune evasion. Together, tumour-intrinsic metabolic adaptation and lactate-mediated microenvironmental reprogramming contribute to resistance to chemotherapy, targeted therapy and immunotherapy. Translationally, metabolic imaging, circulating LDH and lactate-related markers, exosomal glycolytic enzymes, gene-expression signatures and lactylation-related features may improve prognostic assessment, treatmentresponse prediction and patient stratification. These findings support biomarker-guided combination strategies that target tumour metabolism, lactate production or transport and stromalimmune crosstalk alongside standard therapies. This review uniquely integrates direct GC-derived evidence with indirect evidence from non-GC models and clinical trials and grades biomarkers and metabolic interventions according to their translational maturity.

Conclusion: Overall, the Warburg effect represents both a central driver of GC progression and a clinically relevant metabolic vulnerability.