HCC perioperative immunotherapy: Insights from Expert consensus on multidisciplinary collaboration in perioperative immunotherapy for hepatocellular carcinoma (2025 edition)

1. Introduction Despite substantial advances in systemic immunotherapy for advanced hepatocellular carcinoma (HCC), clinical guidance on its use in the perioperative setting remains limited. The perioperative period, which encompasses the neoadjuvant, intraoperative, and adjuvant phases, offers a unique window to improve long-term outcomes by modulating the immune microenvironment, facilitating tumor clearance, and reducing the risk of early recurrence. To address this gap in surgical oncology practice, we convened a multidisciplinary panel comprising the members of the Hepato-Pancreato-Biliary multidisciplinary team (MDT) Professional Committee, Chinese Chapter of the International Hepato-Pancreato-Biliary Association, Group of Liver Surgery of the Chinese Society of Surgery (Chinese Medical Association), and the General Surgery Branch of the Chinese Geriatrics Society. This collaboration resulted in the publication of the Expert Consensus on Multidisciplinary Collaboration in Perioperative Immunotherapy for Hepatocellular Carcinoma (2025 Edition),[1] released in Chinese on June 10, 2025. This document constitutes the first structured effort to comprehensively define the indications, strategies, and safety considerations for perioperative immunotherapy in patients with resectable or borderline-resectable HCC. The consensus outlines therapeutic principles tailored to the surgical timeline, including regimen selection, treatment sequencing, patient stratification, monitoring protocols, and management of immune-related adverse events. It also addresses controversial areas such as immunotherapy rechallenge, hyperprogression, and emerging intraoperative interventions. By addressing a critical gap in clinical practice, this consensus aims to standardize perioperative immunotherapy, foster multidisciplinary coordination, and support ongoing innovation in HCC management. It serves as a timely and pragmatic reference for hepatobiliary surgeons, oncologists, and clinical investigators engaged in curative-intent treatment. Additionally, it provides a foundational framework for international adaptation, particularly in light of the limited perioperative-specific recommendations in current global guidelines such as those from the NCCN[2] and the EASL.[3] Topics outside the scope of the 2025 consensus, such as immunotherapy in transplant-eligible candidates, are discussed only as clearly delineated contextual notes, based on relevant external guidance. 2. Progress and gaps in HCC immunotherapy: the underused perioperative window and the full-cycle management model Immune checkpoint inhibitors (ICIs) have redefined the therapeutic landscape of advanced HCC, with PD-1/PD-L1-based combinations now established as first-line treatments.[4,5] Nonetheless, critical challenges remain, particularly in identifying responders, managing immune-related toxicities, and addressing therapeutic resistance. Although immunotherapy has demonstrated efficacy in tumor downstaging and conversion to resection, its integration into perioperative care remains limited and lacks standardization. Emerging evidence indicates that perioperative immunotherapy, administered in the neoadjuvant or adjuvant setting, may benefit patients with high-risk resectable HCC.[6,7] However, the absence of validated biomarkers and treatment algorithms complicates its clinical implementation. The perioperative period, characterized by low tumor burden and dynamic immune modulation, represents a biologically favorable yet underutilized window for systemic intervention. A dedicated consensus on perioperative immunotherapy is therefore both timely and necessary, offering a structured framework to align systemic innovation with surgical strategies in the context of curative-intent HCC management. 3. From biomarkers to toxicities of immunotherapy in HCC 3.1. Individualized selection and the emerging role of etiology Recent subgroup analyses from landmark trials, including IMbrave150 and HIMALAYA, suggest improved survival outcomes in patients with HBV- or HCV-associated HCC treated with ICIs.[4,8] Although these findings, particularly the pronounced hazard ratios in virally infected subgroups, are compelling, they remain exploratory and warrant cautious interpretation. A key question is whether these outcomes reflect true biological differences or are artifacts of statistical stratification. Mechanistically, chronic viral hepatitis may establish a distinct immune landscape characterized by sustained antigen exposure, differential T-cell exhaustion, and altered interferon signaling, potentially enhancing tumor immunogenicity. However, current evidence is insufficient to support etiology as an independent predictive biomarker. Prospective, stratified trials and integrative immune profiling across etiologies are essential to disentangle meaningful immunologic drivers from confounding epidemiologic variables. Until such data emerge, viral status should guide hypothesis generation rather than clinical decision-making. 3.2. Biomarker development: current status and prospects Despite increasing research, few predictive biomarkers for immunotherapy in HCC have reached clinical utility. Markers such as PD-L1, tumor mutational burden (TMB), and microsatellite instability (MSI), validated in other cancers, have shown inconsistent predictive value in HCC, limited by biological heterogeneity, assay variability, and the lack of prospective validation. Investigations have expanded to include oncogenic pathways (e.g., Wnt/β-catenin, FGFR4) and nontumor influences such as the gut microbiome. Although advanced technologies, including single-cell sequencing and multi-omics approaches, have refined immune classification, most findings remain confined to early-phase studies.[9,10] A central challenge is the disconnect between biomarker discovery and clinical application. Retrospective analyses predominate, and interventional trials rarely incorporate biomarker-driven stratification. To enable translation, standardized tissue handling, longitudinal biospecimen collection, and biomarker-enriched trial arms are essential. In HBV-prevalent regions of Asia, relatively homogeneous patient populations offer an opportunity to evaluate etiology-specific biomarkers in a consistent clinical background. 3.3. Regimen selection: extrapolated practice vs contextual evidence The consensus recommends several ICI-based regimens, such as atezolizumab plus bevacizumab and STRIDE (durvalumab plus tremelimumab), based primarily on efficacy in advanced HCC. However, their application in the perioperative setting lacks direct supporting evidence. Perioperative immunotherapy, which is curative in intent, necessitates different endpoints, including effects on resectability, postoperative hepatic function, and immune modulation under surgical stress, none of which were assessed in the original trial designs. Moreover, biological differences between early- and late-stage tumors complicate extrapolation. In resectable HCC, immune responses may be shaped by lower tumor burden, altered stromal interactions, and distinct cytokine milieus. VEGF inhibition, for example, could impair wound healing or exacerbate intrahepatic hypertension, risks not fully characterized outside advanced disease contexts. Despite these uncertainties, the consensus pragmatically endorses existing ICI combinations as provisional standards, with individualized selection based on liver function, performance status, and treatment tolerability. Although this approach reflects clinical necessity, it highlights the paucity of evidence guiding regimen selection in curative settings. Future studies should prioritize endpoints relevant to surgical outcomes, including margin status, liver functional reserve, and perioperative immune dynamics. Window-of-opportunity trials incorporating paired tissue and blood sampling could clarify immune activation or exhaustion profiles during this critical interval. Until such data are available, caution is warranted in repurposing regimens designed for palliation to contexts where long-term survival is the goal. 3.4. Dynamic response evaluation in perioperative immunotherapy: a framework in progress The consensus proposes a multidisciplinary framework for response monitoring in perioperative immunotherapy, incorporating radiologic, serologic, and pathological parameters. This reflects growing awareness that conventional static imaging alone is inadequate to capture the complexity of immune response. Contrast-enhanced MRI, evaluated using modified RECIST and immune-related RECIST criteria, is prioritized to address challenges such as pseudoprogression.[11,12] Concurrent tracking of alpha-fetoprotein (AFP), protein induced by vitamin K absence-II (PIVKA-II), and exploratory biomarkers such as circulating tumor DNA (ctDNA) is recommended to enhance response assessment. Pathological evaluation following neoadjuvant or conversion therapy is emphasized, given its prognostic relevance for recurrence. Nonetheless, several elements of this framework remain investigational. The clinical utility of ctDNA kinetics lacks standardized thresholds or validated predictive value in HCC. Definitions of pathological response, such as criteria for major response and the prognostic significance of immune cell infiltrates, vary across studies. How these parameters should inform intraoperative timing or adjustment of adjuvant therapy is also unclear. Operationalizing this framework will require biomarker-informed clinical trials that permit real-time treatment adaptation. Protocols enabling escalation, de-escalation, or deferral of surgery based on evolving biological signals could significantly advance precision perioperative care. Although the consensus provides a valuable conceptual scaffold, its practical impact will depend on the establishment of actionable benchmarks and their integration into clinical workflows. 3.5. Combination strategies in HCC: optimizing immunotherapy efficacy through integrated approaches The consensus acknowledges the limited efficacy of ICI monotherapy in HCC, where response rates remain below 20% and durable benefit is uncommon. This has driven the widespread adoption of combination strategies, including ICIs with anti-VEGF agents or dual checkpoint blockade, many of which are now supported by phase III trials (Recommendations 5 and 6). Combinations such as atezolizumab–bevacizumab, camrelizumab–apatinib, and durvalumab–tremelimumab have reshaped first-line systemic therapy, albeit with largely empirical development pathways. Although preclinical data support the role of VEGF inhibition in vascular normalization and immune priming, mechanistic synergy with ICIs in HCC, particularly in cirrhotic immune microenvironments, remains incompletely defined. A potentially transformative approach involves integrating locoregional therapies with systemic immunotherapy. Trials such as EMERALD-1, LEAP-012, and TALENTACE suggest that transarterial chemoembolization (TACE) may enhance ICI efficacy by promoting tumor antigen release and local immune activation.[13,14] However, most trials have demonstrated progression-free survival (PFS) gains without overall survival (OS) confirmation, and questions regarding sequencing, treatment duration, and immune correlates remain unresolved. Future strategies must shift from empirically additive regimens to biologically informed combinations. Biomarker-driven approaches, leveraging tumor genomics, immune phenotyping, or ctDNA, will be critical to personalizing treatment. Adaptive trial designs responsive to early immune or radiologic changes may further refine therapeutic precision. Although the consensus establishes a pragmatic foundation, meaningful innovation will depend on linking mechanistic insights with clinical implementation. 3.6. Balancing benefit and risk: efficacy and irAE management in perioperative immunotherapy The consensus outlines a practical framework for managing immune-related adverse events (irAEs) in the perioperative setting (Recommendations 7–14). Core recommendations include baseline evaluation of hepatic, endocrine, cardiovascular, and pulmonary function; standardized toxicity grading; and MDT oversight. Although conceptually robust, the feasibility of real-world MDT coordination underscores the need for streamlined clinical workflows and clearer delineation of responsibilities. The document provides detailed guidance on organ-specific irAEs, ranging from dermatologic and endocrine events to life-threatening complications such as pneumonitis and myocarditis. Early recognition and prompt corticosteroid initiation remain the cornerstones of management, with escalation to second-line immunosuppressants in refractory cases. Emphasis is appropriately placed on longitudinal monitoring and patient education, given the potential for delayed, recurrent, or surgery-exacerbated toxicities. Notably, the consensus introduces practical recommendations for ICI rechallenge following irAEs (Recommendation 15). Reintroduction of therapy may be considered in patients with resolved grade 1–2 toxicities following MDT review, whereas those with prior grade ≥3 events require stringent risk–benefit evaluation. Although prospective data are limited, this structured approach provides a reasonable interim framework that balances therapeutic continuity with patient safety. 3.7. Immunotherapy resistance and hyperprogression: complexities and clinical implications The consensus classifies resistance to ICIs in HCC as either primary or acquired. Primary resistance is often attributable to intrinsic tumor features, including low neoantigen burden, defective antigen presentation, and immune exclusion driven by aberrant β-catenin or JAK/STAT signaling pathways.[15,16] Acquired resistance typically arises following an initial response and involves adaptive immune evasion mechanisms, such as upregulation of TIM-3, LAG-3, TIGIT, or clonal immune escape.[17] These insights underscore the need for rational combination therapies and biomarker-informed strategies, particularly in perioperative settings. Hyperprogressive disease (HPD), defined by a ≥2-fold increase in tumor growth rate or >50% increase in lesion size on early imaging, occurs in approximately 10%–15% of HCC patients and is associated with poor outcomes.[18,19] Putative predictors include MDM2/MDM4 amplification, EGFR mutations, high neutrophil-to-lymphocyte ratio, and exhausted CD8+ T-cell signatures, although validation remains pending. Recommendation 16 emphasizes the importance of early stratification and individualized surveillance to detect resistance and HPD. Prospective trials incorporating predictive biomarkers will be essential to inform therapeutic adaptations and improve patient outcomes. 3.8. Managing drug interactions in immunotherapy: precision over protocol As combination immunotherapy regimens become increasingly prevalent in HCC, the complexity of drug–drug interactions has expanded in parallel.[20] The consensus highlights the risks associated with regimens such as atezolizumab–bevacizumab and camrelizumab–apatinib, where synergistic efficacy is accompanied by overlapping toxicities, including hematologic suppression, hepatotoxicity, and immune-related adverse events. These risks underscore the need for individualized monitoring, proactive dose adjustment, and early recognition of adverse interactions, rather than reliance on uniform protocols. Importantly, the consensus extends its focus to commonly coadministered non-oncologic agents. Immunosuppressive drugs (e.g., thalidomide) may attenuate immune priming, whereas immunostimulatory compounds, such as thymosin-α1, pose unpredictable risks of autoimmunity. Supplements and traditional medicines, such as herbal extracts, polysaccharides, and antioxidants, are poorly studied in this context but may exert immunomodulatory or hepatotoxic effects, warranting preemptive therapeutic drug monitoring. Specific guidance is also provided for supportive medications. COX-2 selective inhibitors are preferred over nonselective NSAIDs to minimize gastrointestinal and immune-related complications. Proton pump inhibitors should be used with caution, given emerging evidence suggesting potential attenuation of ICI efficacy. Anti-infectives that prolong the QT interval or alter cytochrome P450 enzyme activity require careful selection, especially in patients on multiple concomitant therapies. Vaccination guidance reflects immunologic nuance: inactivated vaccines are recommended before initiating immunotherapy, whereas live attenuated vaccines are contraindicated due to theoretical risks of uncontrolled replication.[21] Collectively, these recommendations support a patient-specific, multidisciplinary approach to medication review, moving beyond general guidelines to precision-based clinical decision-making. 4. Immunotherapy as neoadjuvant and conversion therapy in HCC The consensus highlights growing interest in preoperative immunotherapy for HCC, encompassing both conversion therapy, to enable resection in borderline or advanced cases, and neoadjuvant approaches aimed at reducing recurrence in resectable tumors. Early-phase studies have reported encouraging outcomes, including pathological complete responses with agents, such as cemiplimab and PD-1 inhibitor–based combinations; however, these findings remain preliminary and context-specific. Among available data, the TALENTop phase III trial provides of the with interim a conversion rate for the absence of survival data and stratified subgroup analyses clinical interpretation. trials combinations with hepatic or reflect a shift strategies, although most remain uncontrolled and to long-term outcomes. is is not but validation. biomarker-driven patient selection and lack standardized criteria for pathological response and surgical Moreover, the perioperative setting introduces distinct such as immune-related liver and potential surgical which from those in treatment Recommendation appropriately for prospective trials in to address these of dynamic immune such as ctDNA clearance, and of immune exhaustion, may enhance patient stratification and define perioperative treatment Until such are preoperative immunotherapy in HCC remains a but immunotherapy in HCC: is ongoing The integration of immunotherapy into the intraoperative setting represents a and in the management of HCC, to disease at a of tumor The consensus introduces of (e.g., and using by approaches are designed to tumor and an immune the surgical intraoperative immunotherapy is its theoretical with immune resection immune antigen and tissue that may enhance immune during this critical However, clinical remains in its supporting evidence from preclinical or early-phase trials, and survival endpoints have yet to be several The intraoperative of or during liver standardization. the immunologic of immune the a of immunologic and chronic are not fully meaningful endpoints, whether pathological clearance, immune cell or recurrence suppression, also remains unresolved. The consensus appropriately classifies intraoperative immunotherapy as (Recommendation for its evaluation structured and with and this will require integration of innovation with mechanistic particularly into surgical antigen and immune activation in these be intraoperative immunotherapy may as a distinct tailored to the immunologic of HCC. immunotherapy in HCC: immunotherapy following resection in HCC represents a to early recurrence by disease and immune particularly in patients with high-risk such as or poor tumor from the trial to support this improved survival with However, with the benefit beyond its long-term efficacy and therapeutic regimens, including monotherapy and combinations such as and have shown preliminary activity in early-phase although survival endpoints and patient stratification. trials are ongoing (e.g., and are to clarify the clinical utility of postoperative immunotherapy. Nonetheless, critical questions which patients true How should immune-related and postoperative hepatic be disease or immune profiling enable treatment current evidence the consensus a cautious adjuvant use outside clinical trials (Recommendation a that signals rather than of the therapeutic Future must prioritize precision stratification, integrating clinical risk with dynamic biomarkers such as ctDNA, immune and hepatitis immune these into prospective trial particularly in may validation and support clinical implementation. immunotherapy in HCC remains a in and yet not for will depend not only on trial outcomes but also on a shift multidisciplinary perioperative care. perioperative immunotherapy in HCC: practical As immunotherapy increasingly the perioperative in HCC, multidisciplinary management has from a to a foundational now on the of regimen and on the of across the care from preoperative to postoperative The consensus introduces a framework that timely and standardized This individualized that for immune hepatic function, surgical and Importantly, it addresses a the lack of management and true not conceptual must define and actionable such as immunotherapy based on liver thresholds or care in response to early Recommendation this coordination from to clinical However, on of supporting workflows. that imaging, toxicity monitoring, and surgical real-time decision-making. immunotherapy may further longitudinal care and timely and must that clinical local evidence particularly from will be critical to these pathways full-cycle management is not but it constitutes the framework that whether therapeutic innovation into durable clinical outcomes. The of perioperative immunotherapy will depend as on systemic as on and The 2025 Chinese consensus represents a in HCC management by perioperative immunotherapy as a structured clinical It underscores major that extends beyond static Liver criteria, intraoperative immune activation as a therapeutic opportunity rather than a and real-time as a dynamic linking neoadjuvant and adjuvant decision-making. Collectively, these challenge conventional treatment and suggest for curative-intent The document offers practical recommendations across the perioperative including patient selection, regimen immune and management of immune-related adverse the current paucity of evidence to resectable or borderline cases. recommendations remain extrapolated from protocols, the need for dedicated prospective However, clinical consensus alone is insufficient for implementation. development of and guidelines is essential. of ICI and perioperative risk management will be critical to integration into such regimens may to real-world than a this consensus should be as a emerging immunotherapy with pragmatic of care. impact will depend not only on clinical but also on the care to support full-cycle