BackgroundImmunotherapy has revolutionized the treatment of malignant tumors; however, it may lead to fatal cardiotoxicity. Herein, we explored the mechanisms underlying cardiac side‐effects induced by immune checkpoint inhibitors (ICIs) and proposed a promising therapeutic target.MethodsSerum samples were collected from 168 patients with advanced non‐small cell lung cancer (NSCLC) receiving ICIs treatment or not. Representative ICI (IBI308) was intraperitoneally injected into normal C57BL/6 and congenital immune deficient nude mice. NOD‐like receptor family, pyrin domain containing 3 (Nlrp3) globally knockout mice and gasdermin D (Gsdmd) globally knockout mice were involved in this study. Mice with cardiac‐specific BTB domain and CNC homolog 2 (Bach2) knock‐in and knock‐out were also included. The Cleavage Under Targets and Tagmentation (CUT&Tag) experiment was conducted to identify downstream molecules of BACH2, which was further validated with dual‐luciferase and electrophoretic mobility shift assays (EMSA). A library of small‐molecule products was screened to identify a specific agonist of BACH2, followed by in vivo and in vitro verification.ResultsPatients treated with ICIs had significantly higher cardiac troponin T (cTNT) and interleukin 18 (IL‐18) levels. IBI308 significantly reduced cardiac function, increased cardiac fibrosis, and induced myocyte pyroptosis in wild type mice and T‐cell deficient nude mice. IBI308‐elicited toxicity was reversed by depleting pyroptotic genes Nlrp3 or Gsdmd. Furthermore, cardiac‐specific knock‐in of Bach2 rescued, whereas cardiac‐specific knock‐out of Bach2 exacerbated IBI308‐induced cardiotoxicity and pyroptosis. BACH2 directly bound to the promoter of G‐Rich RNA sequence binding factor 1 (GRSF1) and promoted its transcription, which then activated the nuclear factor κB (NF‐κB) signaling cascade. The protective effect of BACH2 was dismissed after knockdown of GRSF1 or inhibition of the NF‐κB pathway. Lipoic acid was identified as an activator of BACH2 and reversed IBI308‐induced pyroptosis in a BACH2‐dependent manner.ConclusionsICIs treatments caused preclinical cardiac injuries by activating myocyte pyroptosis. BACH2 exerted protective effects by promoting GRSF1 transcription and suppressing pyroptosis. Lipoic acid attenuated ICI‐induced cardiotoxicity by upregulating BACH2, which might be a novel therapeutic strategy.Key pointsImmune checkpoint inhibitors cause elevated cardiac injuries in humans and miceICIs cause myocyte pyroptosis and cardiotoxicity not via the adaptive immune systemBACH2 ameliorates ICIs‐induced pyroptosis through transcriptionally promoting GRSF1.Lipoic acid as a transcriptional inducer of BACH2 suppresses ICIs‐induced cardiotoxicity

BackgroundTissue‐resident macrophages (TRMs) exhibit dual roles in tumor progression, yet their functional reprogramming within the tumor microenvironment (TME) remains a critical unresolved question.MethodsWe integrated single‐cell and spatial transcriptomics from a pan‐cancer atlas of 1.39 million cells across five malignancies with 2,318 bulk RNA‐seq samples to investigate macrophage states. A TRM inflammatory remodeling signature (TIR‐Sig) was developed for clinical biomarker validation.ResultsWe identified a conserved inflammatory TRM subtype (iTRM) characterized by CXCL8/IL1B/IL6 co‐expression that correlates with poor clinical outcomes. Crucially, both TRMs and monocyte‐derived tumor‐associated macrophages (Mono‐TAMs) underwent convergent differentiation into functionally similar inflammatory phenotypes, establishing iTRM as a universal tumor‐educated state. Further integration analysis revealed an iTRM‐enriched TME subtype which featured coordinated infiltration of neutrophils and cancer‐associated fibroblasts (CAFs), forming a ‘cold tumor’ ecosystem associated with immune checkpoint blockade (ICB) resistance and poor prognosis. The derived TRM inflammatory remodeling signature (TIR‐Sig) demonstrated dual clinical utility: it predicted patient survival (HR = 19.86, p < .001) and stratified ICB responders (AUC = .706).ConclusionThis study establishes phenotypic links between tissue‐resident and recruited macrophages through inflammatory reprogramming within TME, provides a unifying framework for pan‐cancer macrophage plasticity in TME, delivers a clinically actionable biomarker suite (TIR‐Sig), and provides potential therapeutic targets for TME remodeling.Key pointsCross‐tissue single‐cell atlas of tissue‐resident macrophages (TRMs).Identification of conserved inflammatory TRM phenotype (iTRM) in pan‐cancer.Dynamic convergence of TRM and monocyte‐derived macrophage lineages.TRM inflammatory remodelling signature (TIR‐Sig) with clinical potential.

BackgroundSkin cancers, including basal cell carcinoma (BCC), squamous cell carcinoma (SCC), cutaneous melanoma (CM) and acral melanoma (AM), exhibit profound heterogeneity in clinical behaviour and therapeutic response. However, how tumour‐immune ecosystems are remodelled across skin cancer types and disease stages, and how these changes influence immune escape and treatment resistance, remain poorly understood.MethodsHere, we integrate single‐cell transcriptomics data from 102 skin cancer samples (including adjacent normal skin, early‐stage and advanced‐stage tumours), with bulk RNA‐seq prognosis cohorts, immunofluorescence staining and in vitro assays to define clinically relevant immune remodelling patterns.ResultsOur analyses identify a malignant NARS2+NDUFC2+ melanoma cell subpopulation, characterised by reduced MHC‐I expression, enriched in advanced‐stage tumours and associated with worse survival and immunotherapy response. CRISPR screening further showed that NARS2 and NDUFC2 are necessary for the proliferation of melanoma cells, highlighting these genes as potential therapeutic targets. Tumour‐associated macrophages (TAMs) originate from both FCN1+ monocytes and FOLR2+ tissue‐resident macrophages, displaying two polarisation states with distinct prognostic associations. Specifically, pro‐inflammatory CXCL9+CXCL10+ TAMs are enriched in SCC, while tissue‐remodelling SPP1+ TAMs are predominant in melanoma. Immunofluorescence staining confirmed that SPP1+ macrophage accumulation correlates with advanced stage, metastasis and poor prognosis in the melanoma cohort. Immune ecotype analysis reveals a transition from ‘T‐cell‐dominant’ ecotypes to ‘desert’ ecotypes as disease advances in BCC, CM and AM. Cell‒cell communication analysis shows that ‘T‐cell‐dominant’ ecotypes have higher MHC‐I signalling pathways in tumour cells, whereas ‘Desert’ ecotypes have higher SPP1+ macrophage signalling, underlining the role of SPP1 on immune remodelling. Functional assays confirm that melanoma cells could drive M2 polarisation and SPP1 upregulation in macrophages. Knocking down or overexpressing SPP1 correspondingly alters M2 gene expression in macrophages.ConclusionsThis study establishes a pan‐skin cancer immune remodelling framework, providing a foundation for biomarker discovery and the development of new immunotherapy strategies.

A central hurdle limiting the success of T‐cell‐based immunotherapies is the progressive dysfunction of T cells, known as exhaustion. Overcoming this exhausted state is therefore a pivotal objective in translational oncology and immunology. The advent of single‐cell multiomics has fundamentally revised the once‐prevailing view of exhaustion as a uniform endpoint. Instead, it is now recognised as a dynamic differentiation process comprising a spectrum of distinct cellular states. This spectrum is organised along a hierarchical axis, originating from progenitor‐exhausted (Tpex) cells that retain proliferative potential and advancing towards terminally exhausted (Tex) populations with severely impaired effector functions. We undertake a comprehensive synthesis of multiomics data—spanning transcriptomic, epigenomic, metabolomic, proteomic and posttranslational modification (PTM)‐proteomic layers—to decipher the interconnected regulatory programmes that dictate commitment along this exhaustion axis. From this integrated analysis, we derive a unified mechanistic framework that delineates the molecular drivers of Tpex cell fate determination and terminal exhaustion. Beyond its explanatory power for basic biology, this framework serves as a direct roadmap for therapeutic innovation, highlighting novel nodes for intervention aimed at reinvigorating the exhausted T‐cell compartment. The practical application of these insights holds significant promise for enhancing the efficacy of established current immunotherapeutic platforms.Key pointsThis review is the first to integrate multi‐omics evidence for constructing a dynamic regulatory map of T‐cell exhaustion.It highlights the critical cross‐omics synergistic mechanisms, such as metabolic reprogramming influencing epigenetic remodeling to drive cell fate.The multi‐omics perspective presented directly informs novel therapeutic strategies.

Efferocytosis is a critical physiological process in which phagocytes clear apoptotic cells to maintain tissue homeostasis. However, within the tumour microenvironment (TME), this process is systematically hijacked by tumour cells, transforming it into a key pathological mechanism that drives immunosuppression, tumour progression and therapeutic resistance. This review systematically elucidates the central role of metabolic reprogramming in this functional reversal, emphasising that efferocytosis is essentially an immunometabolic intersection process precisely regulated by metabolism. By releasing various metabolites such as ATP, lactate, adenosine and sphingosine-1-phosphate (S1P), apoptotic tumour cells not only recruit tumour-associated macrophages (TAMs) but also metabolically pre-program their functions, inducing polarisation towards a pro-tumourigenic M2-like phenotype. During the recognition stage, tumour cells exploit metabolic abnormalities, such as glycosylation and lipid oxidation, to modify surface 'eat-me/don't-eat-me' signals, thereby hijacking macrophage recognition and engulfment programs. Upon completion of engulfment, systemic reprogramming of amino acid, lipid and glucose metabolism occurs within macrophages. These metabolic alterations synergistically lock their immunosuppressive phenotype and establish a metabolic symbiosis between the tumour and stromal cells. Based on these mechanisms, this review further explores translational strategies targeting the efferocytic-metabolic axis, aiming to reprogram the immunosuppressive efferocytosis into immune-activating events to overcome TME-mediated immunosuppression and enhance current therapeutic efficacy. By deeply dissecting the metabolic regulatory networks of efferocytosis, we aim to pave new directions for cancer immunotherapy, achieving a paradigm shift from 'metabolic hijacking' to 'metabolic interventional therapy'.

Acute leukaemia is a highly aggressive malignancy with significant unmet therapeutic needs, partly due to epigenetic dysregulation. Here, we uncover deoxynucleotidyl transferase terminal-interacting protein 1 (DNTTIP1) within the mitotic deacetylase complex (MiDAC) as a previously unrecognised epigenetic regulator crucial for leukaemic cell survival and elucidate its mechanistic and translational significance. Using cellular, biochemical, and genetic perturbations, coupled with validation in multiple in vivo leukaemia mouse models, we characterised DNTTIP1's role in acute leukaemia. An integrated multi-omics analysis incorporating RNA-seq, cleavage under targets and tagmentation (CUT&Tag) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) revealed that DNTTIP1 recruits histone deacetylase 1/2 (HDAC1/2) to silence BCL2-modifying factor (BMF) and drive leukaemogenesis, validated by chromatin immunoprecipitation quantitative PCR (ChIP-qPCR). Drug synergy assays identify poly(ADP-ribose) polymerase (PARP)/HDAC/BCL2 inhibitor combinatorial efficacy. DNTTIP1 depletion impaired MiDAC recruitment in acute leukaemia, leading to histone H3 lysine 27 (H3K27) hyperacetylation at the BMF promoter and reactivating this effector. Upregulated BMF disrupted BCL2-mediated survival, triggering coordinated autophagy and apoptosis. Combined HDAC1/2 and BCL2 inhibition exerts synergistic anti-leukaemic effects, a therapeutic strategy currently under clinical evaluation. Further, PARP inhibition profoundly enhanced this synergy by impairing DNA damage repair, unveiling a novel triple-combination strategy. Our work defines the DNTTIP1‒HDAC1/2‒BMF axis as a pivotal epigenetic vulnerability in acute leukaemia and provides preclinical rationale for targeting this axis. These findings offer a validated biological framework for advancing this targeted combination therapy into clinical trials. DNTTIP1 is overexpressed in acute leukaemia and associated with poor prognosis. DNTTIP1 acts as a scaffold for the MiDAC complex, recruiting HDAC1/2 to silence BMF and inhibit leukaemic cell death. Pharmacological disruption of the DNTTIP1-HDAC1/2-BMF axis impairs leukaemogenesis.

DNA methylation and chromatin accessibility are pivotal epigenetic regulators of gene expression and cellular identity, with significant implications in tumorigenesis and progression. Current single-cell multi-omics methods are limited in throughput and sensitivity, hindering comprehensive biomarker discovery. We developed single-cell split-pool ligation-based multi-omics sequencing technology (SpliCOOL-seq), a high-throughput single-cell sequencing technology that simultaneously profiles whole-genome DNA methylation and chromatin accessibility in thousands of cells. By integrating in situ GpC methylation, universal Tn5 tagmentation, and split-pool combinatorial barcoding, SpliCOOL-seq achieves enhanced sensitivity and scalability. SpliCOOL-seq accurately distinguished lung cancer cell types based on genetic and multiple epigenetic modalities and revealed that the two DNA methyltransferase (DNMT) inhibitors, 5-Azacitidine and Decitabine, both cause large-scale demethylation but in distinct patterns. Applied to primary lung adenocarcinoma, SpliCOOL-seq identified tumour subclones within the tumour lesion and uncovered novel DNA methylation biomarkers (e.g., FAM124B, SFN, OR7E47P) associated with patient survival. Additionally, we demonstrated accelerated epigenetic ageing and mitotic activity in tumour subclones, providing new insights into tumorigenesis. SpliCOOL-seq achieves parallel profiling of whole-genome DNA methylation and chromatin accessibility in the same individual cells in a high-throughput manner and is hopefully used to illustrate regulatory interactions under different cell states. SpliCOOL-seq enables high-resolution, multi-modal epigenetic profiling at single-cell resolution, offering a powerful platform for discovering cancer biomarkers. Its application reveals novel therapeutic targets and early-diagnostic markers, underscoring its potential in precision oncology. SpliCOOL-seq achieves high-throughput single-cell co-profiling of DNA methylation and chromatin accessibility. DNMT inhibitors caused cancer cell demethylation with divergent patterns. SpliCOOL-seq enables the discovery of genes related to LUAD tumorigenesis. Ageing and LUAD tumorigenesis may share similar epigenetic alterations.

Acute kidney injury (AKI) frequently progresses to chronic kidney disease (CKD), but the underlying mechanisms of this transition remain unclear. While TIMP2 is a known biomarker for AKI, its direct pathogenic role in the AKI-CKD transition has not been fully elucidated. TIMP2 expression was evaluated in multiple murine models, including unilateral ischemia-reperfusion injury (UIR), unilateral ureteral obstruction (UUO), and cisplatin-induced nephropathy. To investigate its function, we employed a tubule-specific, inducible TIMP2 knockout mouse model (Ksp-CreERT2; TIMP2fl/fl) and a tubular overexpression model. TIMP2 was significantly upregulated during the AKI-CKD transition across all tested models. Tubule-specific deletion of TIMP2 markedly attenuated renal fibrosis, suppressed senescence-associated secretory phenotypes (SASP), and promoted tubular repair. Conversely, TIMP2 overexpression exacerbated cellular senescence and fibrotic remodeling. Mechanistically, TIMP2 was found to bind to the Wnt co-receptor LRP6, promoting its phosphorylation and subsequent β-catenin signaling activation, a process independent of its canonical matrix metalloproteinase (MMP) inhibitory function. TIMP2 is a central mediator of maladaptive repair that links cell senescence and fibrotic reprogramming via the LRP6/β-catenin pathway. These findings suggest that TIMP2 serves not only as a biomarker but also as a potential therapeutic target for mitigating the AKI-CKD transition. TIMP2 is upregulated in injured renal tubules and promotes maladaptive repair and cell senescence. Genetic deletion of TIMP2 in tubular epithelial cells attenuates renal fibrosis and improves mitochondrial function. TIMP2 activates Wnt/β-catenin signalling by binding to LRP6 via an MMP-independent mechanism.