3568 Background: Early detection of colorectal cancer (CRC) improves survival, but current screening is limited by poor colonoscopy compliance and low cfDNA sensitivity for early-stage lesions and advanced adenomas (AA). Beyond tumor shedding, solid tumors remotely disrupt bone marrow hematopoiesis, inducing systemic genomic instability in hematopoietic lineages. Leveraging this mechanism, we developed a noninvasive detection strategy using genome-wide profiling of DNA remnants in mature red blood cells (rbcDNA). We previously showed that tumor-induced IL-18/NR4A1 signaling drives locus-specific DNA damage in hematopoietic progenitors, generating rbcDNA signatures distinct from shedding-dependent cfDNA and enabling improved detection of early-stage cancer. Here, we report the first multicenter and prospective clinical validation of this rbcDNA-based assay for the detection of early colorectal neoplasia (NCT05875584). Methods: We enrolled 1,251 colonoscopy-confirmed participants (561 non-advanced neoplasia controls (non-AN), 330 AA, 360 CRC). Peripheral blood (1–2 mL) was collected from each participant, and rbcDNA was isolated and sequenced by low-coverage whole-genome sequencing (~2×), as previously described (PMID: 40341742). Participants were randomly assigned (8:2) to discovery and test cohorts. The discovery cohort was used for CRC- and AA-associated rbcDNA features identification and model development, while the test cohort was used for cutoff optimization. This locked model was externally validated in two independent cohorts. A prospective, observational case-control study was also conducted, in which blood and stool samples were collected simultaneously to compare the rbcDNA classifier with quantitative FIT (qFIT). Among 598 enrolled participants, 585 were included in the final analysis (299 non-AN, 206 AA, and 80 CRC). Results: At a predefined 90% specificity, the rbcDNA classifier achieved sensitivities of 85% for AA and 95% for CRC in the test cohort. Across two external cohorts, the assay consistently achieved 80% and 78% sensitivity for advanced colorectal neoplasia, 91% sensitivity for CRC in both cohorts, and 92% and 91% specificity. In the prospective study, rbcDNA yielded 90% sensitivity for CRC and 60% for AA at 90% specificity, with specificity remaining comparable in participants with non-neoplastic findings and non-advanced adenomas. Compared with qFIT, rbcDNA matched overall CRC sensitivity (90% vs. 88%) but outperformed it for stage I CRC (89% vs. 58%) and advanced adenomas (60% vs. 18%), including >50% of large sessile serrated lesions and tubular adenomas (≥1 cm) versus <15% by qFIT. Conclusions: This first prospective clinical study demonstrates that rbcDNA provides a highly sensitive, non-invasive approach for early colorectal neoplasia detection. Clinical trial information: NCT05875584 .

To evaluate the efficacy and safety of fruquintinib combined with chemotherapy as second-line treatment for metastatic colorectal cancer (mCRC), we performed an open-label phase II trial. A total of 102 Chinese mCRC patients who progressed after first-line therapy were enrolled and received fruquintinib plus chemotherapy. Fruquintinib was administered in a standard 4-week regimen or an adjusted 3-week regimen. Primary endpoint was progression-free survival (PFS). Efficacy and adverse events (AEs) were compared to a real-world control group. As of data cutoff on January 10, 2026, with a median follow-up of 33.2 months, the median PFS was 7.1 months (95% CI, 5.4-8.6) and overall survival (OS) was 22.6 months (95% CI, 19.7-26.2). Objective response rate was 27.6% (95% CI: 19.2-37.7), disease control rate (DCR) was 83.7% (95% CI: 74.5-90.1), and median duration of response (DoR) was 11.9 months (95% CI: 8.8-15.0). Patients with primary tumor resection, no liver metastasis, or no prior history of anti-vascular endothelial growth factor (receptor) therapy had improved survival. Grade ≥ 3 AEs occurred in 38.2% of patients, common grade ≥ 3 AEs were neutropenia (11.8%) and leukopenia (5.9%). Compared to the control group, the fruquintinib group showed significantly improved median PFS (6.6 vs. 5.3 months; HR, 0.68, 95% CI, 0.51-0.91; P = 0.010), higher ORR (23.1% vs. 16.9%) and DCR (79.5% vs. 67.7%), and a numerically longer OS (23.0 vs. 19.7 months; P = 0.640). These results showed fruquintinib plus chemotherapy may represent a novel and rational second-line option for mCRC with promising efficacy and favorable safety.

Abstract Background and Aims Acute-on-chronic liver failure (ACLF) is associated with high short-term mortality, but substantial heterogeneity among existing diagnostic and prognostic models results in inconsistent patient identification and risk assessment. We conducted a systematic head-to-head comparison of major ACLF diagnostic and prognostic models to evaluate concordance, short-term mortality prediction and clinical utility, with the goal of informing harmonization of ACLF assessment. Methods We analysed 3,370 patients with acute decompensation of cirrhosis in the COSSH cohort, with external validation in an independent Ambi-Spective cohort from India (n=2,055). Five ACLF diagnostic models were evaluated for identification of patients at risk of 28-day mortality. Reclassification was assessed using net reclassification improvement. Prognostic scores were compared using concordance index, integrated discrimination improvement, calibration, and decision-curve analysis. Results Diagnostic frameworks identified markedly different proportions of ACLF. A-TANGO and COSSH-ACLF classified the largest high-risk populations while maintaining substantial short-term mortality and balanced sensitivity–specificity profiles. Compared with COSSH-ACLF, A-TANGO improved net reclassification by 7.7%, with further gains versus EASL-CLIF (11.8%), APASL-ACLF (36.4%), and NACSELD-ACLF (45.9%). In the external cohort, A-TANGO and COSSH-ACLF showed similar discrimination and identified comparable proportions of patients. Combined application of the two models delineated three clinically meaningful strata, identifying a discordant intermediate-risk group with approximately 11% 28–day mortality. Among prognostic scores, COSSH-ACLF II and A-TANGO OF scores demonstrated strong and complementary performance across cohorts. Conclusions Outcome-anchored ACLF definitions converge in identifying patients at highest short-term risk across diverse populations. Alignment between A-TANGO and COSSH-ACLF, together with identification of an intermediate-risk phenotype, supports a data-driven framework for improving consistency and advancing global harmonization of ACLF diagnosis and risk stratification.

e15635 Background: The neoadjuvant PD-1 inhibitors plus chemoradiotherapy (nCRT) has improved complete response (CR) rates in patients with locally advanced rectal cancer (LARC). However, the optimal radiotherapy strategy—particularly whether simultaneous tumor-focused dose intensification can further potentiate immunotherapeutic efficacy—remains unclear. This study evaluates pucotenlimab combined with dose-intensified nCRT and explores whether this approach enhances tumor response and clinical outcomes in LARC. Methods: This prospective, single-arm phase II study enrolled patients with pMMR/MSS LARC (cT3–4 and/or N+, M0; tumor ≤10 cm from the anal verge). All participants received neoadjuvant, dose-intensified radiotherapy (57.5 Gy in 25 fractions) targeting the primary tumor and involved nodes, combined with concurrent capecitabine and pucotenlimab (anti-PD-1). This was followed by two cycles of consolidation therapy with pucotenlimab plus capecitabine and oxaliplatin (CAPOX). Based on treatment response and patient preference, patients underwent either radical surgery or a watch-and-wait (W&W) strategy. Subsequently, all patients completed four additional cycles of pucotenlimab plus CAPOX. The primary endpoint was complete response (CR), defined as either pathological CR (pCR) or clinical CR (cCR). Results: From August 2024 to December 2025, 36 patients were enrolled. 63.89% (23/36) cases with tumors were located ≤5 cm from the anal verge, including 38.89% (14/36) with ultra-low tumors (≤3cm). High-risk features (T4a/b, mesorectal fascia involvement, positive lateral lymph nodes, N2 disease, or extramural venous invasion) were present in 88.89% (32/36) of patients. At the data cutoff, 24 patients had completed response evaluation after consolidation therapy, 9 underwent surgery and 15 adopted a W&W strategy. The pCR rate among surgical patients was 55.56% (5/9). All 15 patients in the W&W group achieved cCR, resulting in an overall CR rate of 83.33% (20/24). Organ preservation was achieved in 62.50% (15/24) of all evaluable patientsand in 78.58% (11/14) among those with low rectal tumors. No treatment related death was reported. Conclusions: Pucotenlimab plus dose-intensified chemoradiotherapy achieved a high complete response rate with rapid tumor regression after just two consolidation cycles in patients with pMMR/MSS LARC, including those with high-risk and ultra-low tumors. This immunochemoradiotherapy regimen offers strong early tumor control and significant organ-preservation opportunity, particularly for very low rectal cancers. These promising findings warrant further validation in larger, comparative trials. Clinical trial information: NCT06770270 .

Surgical recurrence, defined as the need for reoperation at the anastomotic site, remains a critical challenge in Crohn’s disease (CD) management. This study aimed to identify clinical and molecular risk factors associated with time to surgical recurrence and develop a validated nomogram for individualized risk stratification. 280 patients were included in this study. Integrin αvβ6 expression was quantified via immunohistochemistry in resection specimens using a validated semiquantitative scoring system. Univariate and multivariable Cox regression analysis were used to identify the variables associated with time to surgical recurrence. A nomogram was then constructed based on the above risk factors. Over a median post-resection follow-up of 71.4 months, surgical recurrence occurred in 32 patients (11.4

TPS159 Background: The liver is the most common site of metastasis in colorectal cancer, and liver metastases represent the primary cause of death among these patients. Achieving no evidence of disease (NED) to attain a disease-free state can significantly prolong overall survival. This study aims to evaluate the conversion rate and safety of adding tislelizumab to standard therapy regimens in patients with initially unresectable CRLM. Methods: This study enrolled patients with MSS-type CRLM. After the MDT assessed and confirmed potentially resectable disease, patients were stratified into two cohorts based on RAS status. The RAS wild-type cohort received tislelizumab combined with cetuximab and FOLFOX. The RAS mutant cohort received tislelizumab combined with bevacizumab and CAPOX. The primary endpoint was the conversion rate, and secondary endpoints included objective response rate (ORR), disease free survival (DFS) and safety. This clinical trial was registered at ClinicalTrials.gov (NCT05409417). Clinical trial information: NCT05409417 .

Abstract Background: Colorectal cancer (CRC) causes substantial mortality, yet most cases arise from precursor lesions that are preventable if detected early. Existing non-invasive tests have limited sensitivity for advanced adenomas (AA), leaving a critical gap in early detection. Cytoplasmic DNA, including micronuclei and chromatin fragments, reflects genomic instability and systemic stress. Solid tumors can remotely induce DNA damage in hematopoietic progenitors, generating persistent DNA remnants in red blood cells (rbcDNA). We recently demonstrated that rbcDNA harbors tumor-associated genomic alterations that can detect early cancers with high accuracy. Here, we report the multicenter validation of an rbcDNA-based assay for early colorectal neoplasia detection. Methods: We enrolled 1,251 individuals who underwent colonoscopy with histopathologic confirmation and categorized them into three groups: CRC (n = 360), AA (n = 330), and non-advanced neoplasia controls (non-AN, n = 561). rbcDNA was extracted from 1-2 mL peripheral blood using our established workflow (Sun et al., PMID: 40341742), including red blood cell isolation, rbcDNA purification, library preparation, and low-coverage whole-genome sequencing (∼2×). Participants were randomly assigned in an 8:2 ratio into a discovery cohort and an internal test cohort, with comparable demographic characteristics. The discovery cohort was used to identify CRC- and AA-associated rbcDNA genomic features and to develop an integrated detection model, which was then evaluated in the internal test cohort to determine the optimal classification cutoff. The locked model was externally validated in two independent cohorts from the Second Hospital of Shandong University (n = 80) and Wenzhou Central Hospital (n = 110). Results: At a fixed 90% specificity cutoff determined in the internal test cohort, the classifier achieved sensitivities of 85% for AA and 95% for CRC. External validation in two independent cohorts from Shandong and Wenzhou confirmed consistent performance for colorectal neoplasia, with sensitivities of 78% and 80%, respectively. Notably, in the Wenzhou cohort, rbcDNA also detected AA and early-stage CRC cases that were negative by fecal occult blood testing. Conclusions: Our findings demonstrate that rbcDNA isolated from just 1-2 mL of peripheral blood enables accurate detection of AAs and early-stage CRC, supporting its potential utility for early diagnosis in clinical practice. A larger prospective clinical study (NCT05875584) will further validate the application of rbcDNA in early cancer detection. Citation Format: Xingyun Yao, Haobo Sun, Chengcheng Liu, Yurong Jiao, Xiangxing Kong, Jie Jin, Kefeng Ding, Jun Li, Xiaofei Gao. Genomic signatures in red blood cell DNA enable early non-invasive detection of colorectal neoplasia: A multicenter clinical study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1315.

The objective of this study was to investigate the efficacy and safety of oral tolvaptan for hyponatremia in patients with cirrhosis in China. In this post hoc subgroup analysis of a phase 2 clinical trial of oral tolvaptan for hyponatremia due to cirrhosis, heart failure, and syndrome of inappropriate antidiuretic hormone secretion in China, patients with hyponatremia due to cirrhosis received placebo or tolvaptan for 7 days (15 mg titrated to 30 or 60 mg/day). The primary endpoint was the average daily change in serum sodium level from baseline to days 4 and 7. We enrolled 131 patients (90 males, 41 females) with cirrhosis mainly due to CHB (70.2

Abstract Background: Colorectal cancer (CRC) is a major cause of cancer mortality, yet early detection markedly improves outcomes. Current screening tools like colonoscopy and fecal immunochemical test (FIT) face limitations in accessibility, participation, and sensitivity, particularly for advanced adenomas (AA). Emerging evidence indicates that tumor-derived systemic stress can induce genomic and epigenetic abnormalities in bone marrow, thereby remotely reprogramming hematopoiesis. Consistent with this phenomenon, our previous work revealed that colorectal tumors remotely disrupt the genomic integrity of hematopoietic stem and progenitor cells, and that these alterations presist through erythroid differentiation to generate distinct DNA signatures in mature red blood cells (rbcDNA). Leveraging these rbcDNA signatures, we developed a CRC-rbcDNA based classifier for early detection of CRC and AA. Following multi-center validation, this study presents the first prospective clinical evaluation of the classifier and a head-to-head comparison with quantitative FIT (qFIT), aiming to assess its performance in detecting both early CRC and AA. Methods: We conduct a prospective cohort clinical study (NCT05875584) designed to validate the locked rbcDNA classifier and to benchmark its performance against qFIT. A total of 598 individuals were enrolled, of which 585 samples were available for analysis. These comprised 299 non-CRC controls (non-neoplastic findings, non-advanced adenomas, and limited non-CRC malignancies), 206 AAs (high-grade dysplasia, villous features, or lesions ≥10 mm), and 80 CRCs. All samples underwent rbcDNA isolation, purification, and low-coverage whole-genome sequencing to generate rbcDNA profiles. For each participant, the locked classifier generated an rbcDNA-based predictive score, and qFIT results were collected in parallel. Results: Using the predefined threshold, the rbcDNA assay reached 90% sensitivity for CRC, including over 90% of stage I-II tumors, and detected 60% of AA cases. Among 299 controls, specificity was 90% and remained consistent across clinical subgroups. Performance in the prospective cohort closely matched that of the multi-center validation set and remained consistent across demographic, clinical, and pathological characteristics. Compared with qFIT, the rbcDNA assay achieved similar CRC sensitivity (90% vs. 88%) but substantially improved AA sensitivity (60% vs. 18%). Overall, the rbcDNA assay showed substantially higher sensitivity than qFIT for early-stage CRC and AA, which typically present with low tumor burden, while maintaining similar specificity. Conclusions: This prospective clinical study demonstrated rbcDNA can be a highly sensitive and non-invasive method for early detection of colorectal neoplasia, supporting its promise for integration into clinical screening practice. Citation Format: Chengcheng Liu, Xingyun Yao, Haobo Sun, Yurong Jiao, Xiangxing Kong, Jie Jin, Kefeng Ding, Jun Li, Xiaofei Gao. Non-invasive detection of early colorectal neoplasia using red blood cell DNA profiling: a prospective clinical validation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7623.

Acute-on-chronic liver failure (ACLF) is a complex syndrome characterized by acute hepatic decompensation superimposed on pre-existing chronic liver disease or cirrhosis that is associated with acute worsening of portal hypertension, increased risk of infection, organ dysfunction and high short-term mortality. This Review provides a comprehensive update on definitions, pathophysiological mechanisms, clinical presentation and management of ACLF. The severe hepatic injury in ACLF triggers systemic inflammation, which is driven by damage-associated molecular patterns, gut-derived microbial products, and immunometabolic and functional dysregulation. Immune dysfunction can range from hyperinflammation and hypercytokinaemia to immune paresis, which in turn predisposes patients to infection and organ failure. The principles of ACLF management prioritize ameliorating the acute hepatic insult, managing portal hypertension, preventing organ failure and optimizing patients who are eligible for liver transplantation. Emerging options include novel therapies targeting immune modulation and liver regeneration, therapeutic plasma exchange and artificial liver support systems. Well-defined criteria for prompt interventions and selection of patients for transplantation within the first week after diagnosis — the ‘golden window’ — have improved outcomes of liver transplantation in patients with ACLF. The Kyoto ACLF Consensus reflects global efforts on unifying definitions, simplifying treatment end points, refining prediction tools, and filling the void of targeted non-transplantation interventions to improve outcomes in patients with ACLF; however, large knowledge gaps remain and further research is needed. Acute-on-chronic liver failure (ACLF) is a complex syndrome characterized by acute hepatic decompensation superimposed on pre-existing chronic liver disease or cirrhosis. This Review provides an update on definitions, pathophysiological mechanisms, clinical presentation and management of ACLF.

We aimed to demonstrate a novel caudal-dorsal approach laparoscopic right hemicolectomy (LRH) for a patient diagnosed with right colon carcinoma. We performed a LRH with a caudal-dorsal approach. We started the operation from the distal root of the small intestine mesentery and the backside of the ascending colon. The ileocolic artery and vein were transected at the dorsal side of the mesocolon. The superior mesenteric vein (SMV) and the gastrocolic trunk were dissected from the dorsal approach. The study adhered to the IDEAL. We followed the recommendations of the LAP-VEGaS Consensus for the reporting of Laparoscopic Videos [1]. The operation lasted approximately 120 min, with an intraoperative blood loss of only 10 mL. Postoperative pathology showed pT1N0M0 (18 lymph nodes resected, all negative for metastasis). The patient was discharged on postoperative day 5 without complications. The caudal-dorsal approach for LRH represents a novel surgical method, and we believe it offers several advantages over traditional approaches.

Background & aimsPatients who do not meet the criteria for Acute-on-Chronic Liver Failure (ACLF) at admission still face a high risk of disease progression and mortality. This study aimed to develop and validate a machine learning-derived clinical tool for the early identification of HBV-pre-ACLF.MethodsWe analyzed 1,682 patients experiencing acute deterioration of HBV-related chronic liver disease but without ACLF. By random forest and SHAP analysis, we identified key predictors of ACLF onset within a 7-day window. We then validated the diagnostic thresholds in a test cohort of 260 patients.ResultsTotal bilirubin (TBIL) and INR were identified as the most critical predictors of ACLF progression. We established optimal diagnostic thresholds at TBIL ≥131.5 μmol/L and INR ≥1.35. Two sequential criteria were developed: pre-ACLF-O (meeting either threshold) for highly sensitive screening, and pre-ACLF-A (meeting both thresholds) for risk confirmation. In the derivation cohort, pre-ACLF-O achieved 98.3% sensitivity, while pre-ACLF-A predicted a 33.09% positive predictive value. These results were successfully validated in the test cohort, where pre-ACLF-O maintained 100% sensitivity and pre-ACLF-A demonstrated a 37.04% positive predictive value.ConclusionsThis dual-indicator tool easily and effectively identifies HBV-pre-ACLF. Using these criteria sequentially provides a practical strategy for early risk stratification, allowing clinicians to initiate timely interventions for high-risk patients.

Drug-induced liver injury (DILI) with severe DRESS carries high mortality, yet rescue therapies for corticosteroid-refractory cases remain undefined. We hypothesized that JAK inhibition could reverse refractory liver injury by targeting the underlying cytokine storm. In this prospective proof-of-concept study, consecutive patients with severe DRESS-associated DILI refractory to corticosteroids (persistent/worsening liver injury) received oral tofacitinib rescue. Key assessments were the normalisation of liver biochemistries. Despite initial corticosteroids, all four patients exhibited progressive severe injury (median peak ALT 1126 U/L). Tofacitinib rapidly reversed liver injury in all cases. Transaminases normalised or near-normalised (median: 48 days), total bilirubin normalised, and cutaneous symptoms resolved completely. Notably, baseline positive autoantibodies seroconverted to negative. No severe adverse events occurred (median follow-up: 274 days). Tofacitinib shows promise as a rescue strategy for corticosteroid-refractory DILI with severe DRESS. The rapid recovery underscores the JAK-STAT pathway's pathogenic role in this setting.

92 Background: Microsatellite stable (MSS) locally advanced rectal cancer (LARC) is refractory to immune checkpoint inhibitors. Our prior Phase II trial demonstrated remarkable efficacy, suggesting short-course radiotherapy (SCRT) plus chemotherapy acts as a potent immunogenic primer for PD-L1 blockade (via subcutaneous envafolimab). We conducted this multicenter, randomized Phase III trial (PRECAM-R) to validate if this patient-centric strategy, combining SCRT, chemotherapy, and immunotherapy, improves outcomes versus standard care. Methods: Patients with resectable, stage II/III (cT3-4a/N+) MSS LARC were randomized (1:1) to the Experimental Group (SCRT 5×5 Gy, then only 2 cycles CAPEOX plus subcutaneous envafolimab) or Control Group (SCRT then CAPEOX). Total mesorectal excision (TME) was performed following neoadjuvant therapy. The primary endpoint was pCR (ypT0N0). Secondary endpoints included tumor regression grade (TRG), Neoadjuvant Rectal (NAR) score, and safety. This pre-specified interim analysis was triggered after 58 patients completed surgery. Results: Fifty-eight eligible eligible patients were randomized (n=29 per arm). Baseline characteristics were well-balanced; 77.6% had Stage III disease. The Experimental Group achieved a pCR rate of 44.8% (13/29), significantly tripling that of the Control Group (13.8% [4/29]; P = 0.0195). Major pathological response (TRG 0-1) rates were 72.4% vs. 51.7% (P = 0.176). The Experimental Group showed superior distribution of tumor downstaging based on NAR scores ( P = 0.036). Notably, early distant metastasis occurred in 13.8% (4/29) of patients in the Control Group (liver/lymph nodes) compared to 0% in the Experimental Group. The addition of envafolimab was well-tolerated, with Grade 3-4 adverse events comparable to the control arm (3.4% vs. 0%, P > 0.99). Crucially, this strategy did not compromise surgical safety, showing no increase in operative complexity or postoperative complications (10.3% vs 13.8%, P > 0.99). Conclusions: This regimen, featuring a patient-centric short-course backbone, shows promise in overcoming resistance to PD-L1 blockade in MSS LARC. This strategy yields high pCR rates and tumor regression with high compliance and a favorable safety profile. The early signal for systemic control positions this convenient regimen as a compelling option for organ preservation. Clinical trial information: NCT05752136 . Interim efficacy and safety outcomes. Endpoint Experimental (n=29) Control (n=29) P Value Primary Endpoint pCR (ypT0N0), No. (%) 13 (44.8) 4 (13.8) 0.0195 Secondary Endpoints MPR (TRG 0-1), No. (%) 21 (72.4) 15 (51.7) 0.176 Median NAR Score (IQR) 8.43 (0.94-8.43) 8.43 (6.66-14.98) 0.036 Distant Metastasis, No. (%) 0 (0) 4 (14.8) 0.112 Grade 3-4 Adverse Events, No. (%) 1 (3.4) 0 (0) 0.99 Postoperative Complications, No. (%) 3 (10.3) 4 (13.8) 0.99

Background Acute-on-chronic liver failure (ACLF) is a life-threatening syndrome involving dysfunction of multiple immune cell types.Objective This study aimed to comprehensively depict the dynamic trajectory of immune responses throughout the disease course of HBV-related ACLF (HBV-ACLF).Design Single-cell RNA sequencing and single-cell proteomics were performed on the peripheral blood mononuclear cells of 45 samples from 17 patients who were hospitalised (progressive/stable/recovering course of HBV-ACLF, 6/5/6) and 15 control subjects (liver cirrhosis, chronic hepatitis B and healthy controls, 5/5/5). Functional and mechanistic experiments were validated in vivo and in vitro.Results Single-cell multiomics analysis revealed specific changes in the peripheral immune response in ACLF. VCAN+CD14+-monocytes with activated interferon-stimulated genes and enhanced inflammatory functions, stimulated by HBV relapse and expanded in ACLF-1, fuelling early inflammatory storm. The subsequent apoptotic hepatocytes predominantly induce hyperinflammatory C-X-C motif chemokine receptor 2 (CXCR2)+-neutrophils and CD163+-monocytes, enriching in patients with progressive ACLF and serving as significant markers of disease deterioration. Cytotoxic T-cells were functionally impaired and significantly decreased in progressive patients. CXCR2+-neutrophils exhibited immunosuppressive activity and induced the exhaustion of cytotoxic T-cells. Pharmacological inhibition of CXCR2 significantly reduced neutrophils infiltration, restored cytotoxic T-cells and showed therapeutic effect in ACLF mice. Six immune cellular modules (CMs) were identified for patient stratification, with CM2 and CM6 showing strong predictive value for disease outcomes, and CM3 indicating a potential early therapeutic window.Conclusion Our longitudinal multiomics study revealed the dynamic evolution of the immune response in HBV-ACLF and characterised diverse immune patterns for the future precise management and therapeutic intervention.