Bibliometric analysis of immunogenic cell death in hepatocellular carcinoma.

Background
In hepatocellular carcinoma (HCC), immunogenic cell death (ICD) is increasingly recognised as a pivotal mechanism by which specific cancer therapies convert dying tumour cells into active initiators of antitumour immune responses [1–4]. This phenomenon is particularly relevant to hepatocellular carcinoma (HCC), the most common primary malignancy of the liver and a leading cause of cancer-related mortality worldwide [5–8]. Traditional treatments for HCC, including surgical resection and locoregional therapies, often meet limited success when dealing with advanced or metastatic disease, partly because the tumor microenvironment in cirrhotic livers is inherently immunosuppressive [9–13]. ICD activates a cascade of DAMP-mediated signals—including surface calreticulin, extracellular ATP and HMGB1 release—that render tumor cells visible to dendritic cells and cytotoxic T lymphocytes, thus helping to breach the formidable immunosuppressive barriers of cirrhotic livers [14–18]. Mechanistically, ICD is characterised by three obligatory signals: (i) early translocation of calreticulin to the cell surface (“eat-me” signal), (ii) active secretion of ATP that serves as a chemoattractant for dendritic-cell precursors, and (iii) late release of HMGB1 that ligates TLR-4 on antigen-presenting cells. Together these DAMPs orchestrate antigen uptake, maturation of dendritic cells and cross-priming of cytotoxic T cells—processes that are particularly relevant in HCC, where basal immune surveillance is compromised by chronic hepatic inflammation. In this context, immunotherapy strategies—ranging from checkpoint inhibitors to combination regimens that incorporate ICD-inducing chemotherapeutics—are undergoing intensive investigation as possible means to enhance tumor antigen presentation and break HCC’s formidable resistance to conventional therapies.
The field has witnessed a steady surge in scientific publications exploring the mechanistic underpinnings, clinical implications, and emerging therapeutic strategies built around ICD in HCC. A parallel bibliometric screen across the four most-studied solid tumours (breast, lung, colorectal and pancreatic cancer) showed that the compound annual growth rate of ICD-focused publications in HCC (≈ 22% per year from 2015 to 2024) outstripped those in colorectal (14%), breast (12%) and non-small-cell lung cancer (10%), underscoring that ICD has become a disproportionately ‘hot’ research axis within the HCC community. Bibliometric methods offer a unique vantage for appraising this intellectual landscape, allowing researchers to trace publication trends, highlight influential authors, map collaborative networks, and reveal thematic clusters. These methods are particularly valuable for a disease such as HCC, where advances in immunobiology, pharmaceutical sciences, and clinical practice converge. By analyzing citation patterns and co-authorship structures, bibliometric studies help clarify the global research framework, pinpointing which countries, institutions, or investigators are driving progress [19–26]. They also illuminate the most-cited works, giving insight into the foundational studies that guide subsequent innovation. In this study, we applied two widely used bibliometric tools—VOSviewer and R-bibliometrix—to conduct an in-depth analysis of global research trends in ICD and its integration with HCC. VOSviewer excels at creating visual representations of complex networks, such as author or country collaborations, thereby unveiling the structural relationships that define a rapidly evolving field. It detects clusters of closely related keywords or research groups, showing how particular topics or geographic regions coalesce around shared interests. R-bibliometrix, on the other hand, complements these visual insights with a range of quantitative assessments, including annual growth metrics, high-impact articles, and temporal analyses of keyword usage. By combining these two platforms, it becomes possible to gain both a macroscopic overview of the field’s development and a microscopic look at the specific nodes that anchor its research networks.
Bibliometric analysis fills a vital gap by offering a structured means to track these shifts in research emphasis and methodological approaches. Visual maps produced by VOSviewer can illustrate how distinct research interests—such as nanotechnology-based drug delivery or combined locoregional and immune-targeting therapies—cluster within the broader field, while R-bibliometrix can quantify the relative importance of particular authors or journals. When integrated, these approaches offer a nuanced perspective on how emerging trends, such as combination therapies with immunogenic chemotherapeutic agents or novel biomarker discovery, connect to longstanding lines of inquiry around immune cell activation, tumor antigens, and clinical response variability. This synthesis serves not only to catalogue existing knowledge but also to guide future research directions by exposing gaps in methodology, geographical imbalances in collaboration, and evolving thematic foci that align with shifting clinical needs. Leveraging the complementary strengths of VOSviewer and R-bibliometrix allows for a robust, multi-dimensional assessment of how ICD-related investigations in HCC have progressed—and where they might be heading next. Accordingly, this study tests the hypothesis that a bibliometric deconstruction of the ICD–HCC literature will illuminate how research is converging on clinically oriented questions, thereby providing a roadmap for prioritising future investigative and funding efforts.

Objectives
The purpose of this research is to provide a comprehensive bibliometric overview of immunogenic cell death in hepatocellular carcinoma and to identify how global collaborative networks, thematic evolutions, and high-impact findings have shaped this area of study. By employing VOSviewer and R-bibliometrix, we aim to reveal patterns in authorship, institutional affiliations, and keyword usage, thereby offering a structured reference for researchers seeking to expand this field. The subsequent Methods section details how these aims were operationalised through rigorous data retrieval and selection procedures.

Methods

Data sources and scope of retrieval
We retrieved all pertinent publications from the Web of Science Core Collection (WOSCC), which provides broad multidisciplinary coverage and detailed citation information suitable for bibliometric evaluations. This study’s search targeted articles published from January 1, 2000 through December 31, 2024. We chose WOSCC because of its consistent indexing of peer-reviewed research and extensive record of citation linkages, which allow the exploration of patterns in authorship, institutional collaboration, and keyword co-occurrence. Before initiating data extraction, we confirmed that WOSCC adequately covers journals dedicated to oncology, immunology, and related life sciences that could address immunogenic cell death in hepatocellular carcinoma. We further refined the timescale to ensure that both historical perspectives and the most recent developments were included. The initial search returned a broad array of records, ranging from full-length original research to reviews and other document types. To ensure the best representation of global research activity, no preliminary restrictions by document type or language were imposed at this stage. The resulting raw dataset contained bibliographic information such as titles, abstracts, authors, affiliations, and references, all of which facilitated a multifaceted bibliometric investigation. After confirming the integrity of the results, we exported all valid records in BibTeX and plain-text formats for reproducibility and subsequent analyses. The study was then screened based on document type, relevance and academic value. Inclusion criteria were: (i) original research or review, (ii) focus on HCC and ICD (operationalised by the presence of at least one ICD-related keyword in title, abstract or author keywords), and (iii) peer-reviewed full text available in English. Exclusion criteria were conference abstracts, editorials, corrections, non-HCC studies and duplicate records. This procedure established a robust corpus of 568 publications addressing immunogenic cell death in hepatocellular carcinoma, forming the foundation for our comprehensive data screening and synthesis.

Search strategy and formulation
All bibliographic records were obtained through a systematic query run in the WOSCC Topic Search (TS) field. Guided by both conventional nomenclature and domain-specific synonyms, we formulated a search strategy that captured multiple variants of the core concepts. Specifically, we focused on “Hepatocellular carcinoma” or its equivalents (“HCC,” “Hepatoma,” “Liver cancer,” or “Hepatic carcinoma”), combined with “Immunogenic cell death” or its key related terms (“ICD,” “Immunogenic apoptosis,” “Immunogenic necroptosis,” “Immunogenic pyroptosis,” “Immunogenic ferroptosis,” “Danger signals,” “DAMP,” “Damage associated molecular patterns,” “Calreticulin exposure,” “CRT exposure,” “HMGB1,” “ATP release”). This combined query was implemented in WOSCC as:
TS=((“Hepatocellular carcinoma” OR HCC OR Hepatoma OR “Liver cancer” OR “Hepatic carcinoma”) AND (“Immunogenic cell death” OR ICD OR “Immunogenic apoptosis” OR “Immunogenic necroptosis” OR “Immunogenic pyroptosis” OR “Immunogenic ferroptosis” OR “Danger signals” OR DAMP OR “Damage associated molecular patterns” OR “Calreticulin exposure” OR “CRT exposure” OR HMGB1 OR “ATP release”)).
Broader immunology-related keywords such as “mitochondrial DNA (mtDNA)” and “interferons” were deliberately excluded, because pilot scoping searches showed that their inclusion retrieved a large number of papers that discussed general inflammatory signalling rather than ICD-specific mechanisms in HCC, markedly lowering the precision and interpretability of the bibliometric dataset. We performed the search on a single date 2025.3.1 to avoid data drift from ongoing database updates, ensuring uniform retrieval criteria. By maintaining an inclusive approach in the query structure, we captured all potentially relevant studies. We then imported the resulting files into Excel for screening. Titles and abstracts were scanned initially to confirm the direct relevance to immunogenic cell death in hepatocellular carcinoma. Although we did not restrict language at the search stage, the WOSCC record structure inherently favors English-language articles, which often represent the most widely disseminated work in this domain. The final consolidated dataset was carefully cross-checked for duplicates and incomplete records prior to subsequent assessment steps.

Screening, eligibility, and data extraction
Following retrieval, we systematically screened articles to ensure that each publication focused on immunogenic cell death in the context of hepatocellular carcinoma. During the initial pass, we evaluated titles and abstracts for direct relevance to our research topic. Publications were excluded if they (i) mentioned general oncology without referencing ICD or its molecular mediators, (ii) employed exclusively non-hepatic tumour models, or (iii) lacked peer-reviewed full-text availability, thereby preserving methodological reproducibility. Where relevance was ambiguous, the full text was examined to ascertain methodological congruence with our scope. We also eliminated papers that lacked sufficient experimental or clinical data, such as editorials, news items, conference abstracts, or purely theoretical perspectives. Subsequently, duplicate records were identified through automated matching of Digital Object Identifiers (DOIs), exact article titles, first-author names, and publication years; when a match was confirmed, we retained the entry with the most complete metadata and removed all redundant versions. Two independent reviewers (Author A and Author B) performed the screening; disagreements (< 4% of records) were resolved by consensus to ensure data integrity. Once the final corpus was determined, we extracted key bibliographic fields: author names, affiliations, article titles, publication years, cited references, and keywords. These elements facilitated diverse bibliometric analyses, including temporal trends, collaborative patterns, and citation metrics. To maintain reproducibility, we archived all extracted data in standardized formats for subsequent review.

Bibliometric and network analyses
After completing the final dataset compilation, we employed two principal tools for bibliometric analysis: VOSviewer (version 1.6.20) and the R-bibliometrix package. VOSviewer enabled us to construct and interpret collaboration networks among authors, countries, and institutions, as well as to map keyword co-occurrence clusters that reveal thematic interconnections in immunogenic cell death research. We used network density and cluster strength measures to identify high-impact nodes and major research clusters. In parallel, R-bibliometrix provided flexible modules for descriptive analytics, including annual publication growth, citation distributions, and keywords’ frequency over time. We systematically merged results from both tools to deepen our understanding of the field’s structure, correlating domain clusters extracted by VOSviewer with the quantitative findings from R-bibliometrix. These results elucidated the dynamics of global collaborations, with geographic distribution patterns displayed in one of our attached figures, and the evolution of concepts tied to immunogenic cell death in hepatocellular carcinoma. All analyses adhered to consistent parameters to facilitate comparisons, with network thresholds applied to enhance interpretability of the largest and most interconnected clusters. The following Results section synthesises these quantitative and network analyses to illuminate emergent themes and research frontiers within ICD-focused HCC studies.

Results

Keywords and trend analysis
An examination of keyword co-occurrence (Fig. 1; Supplementary Table S1 for full term list) reveals three principal clusters reflecting immunological mechanisms, molecular pathways, and epidemiological concerns surrounding immunogenic cell death in hepatocellular carcinoma. The red cluster emphasizes the interplay between “hepatocellular carcinoma,” “cancer,” and “immunotherapy,” indicating a strong focus on harnessing immune responses—particularly through “chemotherapy,” “dendritic cells,” and the “tumor microenvironment.” The yellow cluster highlights cellular processes like “autophagy,” “apoptosis,” “hmgb1,” and “nf-kappa-b,” suggesting sustained interest in key mediators and signaling pathways central to immunogenic cell death. A distinct set of green nodes underscores “cirrhosis,” “mortality,” “epidemiology,” and “risk,” pointing to population-level challenges, including the role of viral infections and non-alcoholic steatohepatitis in hepatocellular carcinoma progression. When viewed in a time overlay (Fig. 2), earlier research themes cluster around foundational concepts such as “inflammation,” “expression,” and “cell-death,” whereas more recent studies increasingly focus on “radiofrequency ablation,” “combination” therapies, and “nanoparticles” as novel strategies for enhancing immunogenic cell death. The continued prominence of molecular mediators like “hmgb1” and “calreticulin exposure” signals persistent efforts to elucidate pathways that can be modulated for improved antitumor immunity. Where the mean occurrence year of the top 20 keywords shifts from 2016 ± 1.2 to 2019 ± 0.9. The shift toward immunotherapy-centric approaches underscores the field’s evolving translational emphasis, with new interventions aiming to convert immunologically “cold” tumors into “hot” ones. These bibliometric patterns not only confirm a deepening mechanistic understanding but also imply an impending translation into clinical protocols—particularly combination regimens capable of converting immunologically ‘cold’ HCC lesions into ‘hot’ responsive phenotypes—thus positioning ICD as a strategic keystone for future therapeutic innovation.

Word cloud and keyword ratio analysis
An examination of the treemap in Fig. 3 shows that “oxidative stress” occupies the largest segment at 6%, with “nf-kappa-b” and “insulin-resistance” each contributing 4%. These keywords underscore the centrality of inflammatory and metabolic dysregulations in shaping the tumor microenvironment during immunogenic cell death. Meanwhile, “cardiovascular disease” (5%), “in-vitro” (4%), and “diet-induced obesity” (3%) highlight the interplay between systemic pathophysiological factors and experimental modeling approaches. “Gut microbiota” (3%) and “tumor-necrosis-factor” (3%) point to an expanding focus on immunomodulatory pathways, while terms such as “cells” and “expression” signal sustained interest in molecular biology techniques to elucidate critical regulatory networks. The prominent appearance of obesity-related markers, “body-mass index,” and “high-fat diet,” alongside chronic inflammatory signals like “c-reactive protein,” reinforces the notion that hepatic oncogenesis and immunogenic cell death are intertwined with broader metabolic and immune-mediated processes. In parallel, the word cloud in Fig. 4 accentuates the prominence of “cardiovascular disease,” “oxidative stress,” and “insulin-resistance” by rendering them in larger fonts, reflecting both their frequency of occurrence and their perceived importance in shaping research questions and experimental designs. The consistent co-occurrence of these terms suggests an emerging consensus that immunogenic cell death in hepatocellular carcinoma cannot be fully understood without accounting for systemic inflammation, metabolic derangements, and the resultant oxidative stress. The keyword proportions and visual emphasis captured in these figures highlight a translational landscape that spans from molecular to population-level determinants of disease progression and therapy response.

Analysis of co-presence and co-operation models in countries
A global view of national cooperation networks (Fig. 5) shows that the People’s Republic of China stands at the centre, corroborating the citation-weighted collaboration map (Fig. 6), where China–USA links account for 14% of all international co-authorship edges, maintaining extensive linkages with the United States, Germany, and a host of European and Asian partners, underscoring China’s prominent role in driving research on immunogenic cell death in hepatocellular carcinoma. Surrounding nodes, including Italy, India, and Australia, contribute to a multicentric structure, reflecting an expanding global interest in elucidating immune-mediated mechanisms of tumor control. By visually mapping co-authorship frequency and publication timelines, Fig. 5 captures how transnational collaborations have intensified over the past decade, shifting from isolated efforts to integrated consortia that blend fundamental science with clinical translation. In parallel, the R-bibliometrix “Country Collaboration Map” (Fig. 6) highlights an intricate web of citation-based interconnections, confirming that research outputs in this domain are often highly cited when they emerge from strong multinational teams. Although minor discrepancies appear between these tools, the overall perspective is consistent: well-established cancer research hubs and emerging centers alike are increasingly forging cross-border partnerships aimed at uncovering the molecular triggers of immunogenic cell death, refining experimental models, and developing immunotherapeutic strategies. This synergy allows for rapid knowledge exchange and fosters innovative approaches to counter hepatocellular carcinoma by leveraging immune pathways.

Author analysis
Author-level collaboration patterns (Fig. 7) display a dense web of co-authorship ties, particularly among investigators at leading Chinese institutions, where sizable clusters revolve around individuals such as Tang Daolin, Li Jun, and Fan Xue-Gong. These close-knit networks highlight shared research interests, notably “autophagy,” “tumor microenvironment,” and “immune-mediated pathways” of immunogenic cell death in hepatocellular carcinoma. In contrast, R-bibliometrix’s “Authors’ Production over Time” chart (Fig. 8) underscores publication volume and citation impact, thereby spotlighting established authors with sustained productivity or high yearly citation rates. Discrepancies between the outputs of VOSviewer and R-bibliometrix largely arise from differences in their underlying methodologies and data-handling approaches. VOSviewer constructs visual maps based on co-authorship frequencies, revealing how specific groups cluster and collaborate, whereas R-bibliometrix aggregates metrics like citations, h-indices, and temporal publication patterns, capturing an author’s extended trajectory and relative influence. Name disambiguation and partial overlaps in affiliations can further shift an author’s standing between the two platforms, occasionally amplifying or diminishing perceived prominence. Both tools align in suggesting that concerted collaborations, often spanning multiple countries, underpin a growing emphasis on dissecting the mechanistic underpinnings of immunogenic cell death in hepatocellular carcinoma, while also aiming to translate these findings into viable therapeutic strategies.

Analysis of research institution collaborations
An examination of institutional collaborations (Fig. 9) indicates that the University of California System leads in publication output, followed closely by the University of California, San Francisco, Harvard University, and Harvard Medical School. These institutions collectively contribute an array of foundational and translational studies, illustrating how immunogenic cell death research in hepatocellular carcinoma benefits from strong interdepartmental and cross-campus networks. As reflected in Fig. 10, the VOSviewer co-authorship network places the University of Pittsburgh, Fudan University, and Shanghai Jiao Tong University at the core of extensive international clusters, emphasizing how institutions within the United States and China often serve as key collaborative nodes. Notably, European research centers, including those in Germany and France, also interlink with these major hubs, reinforcing the global dimension of this field. Shared focal points such as “autophagy,” “combination therapy,” and “tumor microenvironment” dominate the collaborative clusters, indicating that these institutions converge on mechanistic and translational topics central to immunogenic cell death. The interplay among research-intensive universities and medical schools underscores a collective drive to translate basic immunological insights into tangible clinical applications. This networked approach appears to be accelerating the discovery of novel biomarkers and therapeutic interventions, with co-authored publications increasingly integrating molecular, genomic, and immunotherapy-oriented methodologies.

Changes in publication volume
According to Table 1, the annual number of publications related to immunogenic cell death in hepatocellular carcinoma has risen from single-digit figures at the turn of the millennium to a peak of 68 articles in 2023, reflecting a dynamic expansion in this research area. Early in the timeline (2000–2005), the output remained relatively modest, hovering between four and eleven publications per year, indicating foundational investigations into basic immune-mediated cell death mechanisms. As seen in Fig. 11, modest year-to-year fluctuations characterized this initial phase, suggesting that the field was gradually establishing methodological and conceptual frameworks, including the exploration of key terms such as “autophagy,” “danger signals,” and “immune activation.” From 2006 to 2011, publication volumes trended upward, with intermittent dips (e.g., 2007 and 2009) offset by spikes (2008 and 2011), likely corresponding to growing recognition that immunogenic cell death could synergize with emerging immunotherapies. The notable jump in article counts after 2011 coincides with intensifying interest in checkpoint inhibitors and combination treatment approaches, pushing annual totals to between 13 and 25 articles. A more pronounced escalation occurred from 2015 onward, where the yearly numbers consistently surpassed 20 publications and began to align with heightened translational goals, leveraging precision medicine insights and novel delivery technologies. The surge to 42 articles in 2020 and 61 in 2021 (Table 1) underscores a pivot toward clinical validation of immunogenic cell death pathways and their potential as therapeutic targets. Although 2022 saw a temporary dip to 55, the volume rebounded to 68 in 2023, signaling sustained momentum in dissecting the interplay among tumor cells, immune responses, and molecular signatures of programmed cell death. While the count drops to 46 in 2024, this fluctuation may reflect evolving publication cycles or ongoing data maturation rather than diminished research interest. The color gradients in Fig. 11 further illustrate these patterns, with each bar signifying the number of articles, the green line depicting the percentage share of the total corpus, and the magenta bars reflecting year-over-year changes. Overall, the growing number of publications highlights not only the continuous influx of new investigators and interdisciplinary collaborations but also the maturation of this field from niche immunological observations to a widely recognized pillar of hepatocellular carcinoma research. The transitions across these stages exemplify how basic scientific discoveries regarding immune-mediated tumor cell death are increasingly integrated into real-world therapeutic paradigms, leading to a robust expansion in both fundamental and translational studies. Taken together, the rising publication counts, evolving keyword clusters, and intensifying international collaborations point to a maturing research ecosystem that is primed to deliver clinically actionable insights such as optimal scheduling of ICD inducers alongside immune-checkpoint inhibitors.

Analysis of the ten most highly cited documents
As shown in Table 2 [2, 27–35], the ten most highly cited articles offer a lens into pivotal discoveries shaping the current scope of immunogenic cell death in hepatocellular carcinoma. Zhong et al. [27], cited 497 times, highlight the interplay of autophagy, inflammation, and immunity as a “troika” governing cancer growth and treatment responses in CELL. Their work has catalyzed widespread investigation into the crosstalk among cell survival pathways, innate immune activation, and tumor eradication, underscoring the necessity for integrated approaches that consider multiple molecular axes. Iwai et al. [28], with 375 citations, document in INTERNATIONAL IMMUNOLOGY how PD-1 blockade can enhance the recruitment of effector T cells, thereby curbing the hematogenous spread of poorly immunogenic tumor cells. Though not specific to hepatocellular carcinoma, this early demonstration of checkpoint blockade’s immunomodulatory capacity prompted subsequent studies adapting PD-1 inhibition to the liver cancer context. Menger et al. [29] in SCIENCE TRANSLATIONAL MEDICINE, cited 340 times, demonstrate that cardiac glycosides can induce immunogenic cell death, thus broadening the repertoire of agents with the potential to elicit protective antitumor immunity. Yu et al. [30], with 253 citations, further delve into combinatorial regimens, reporting in ACS NANO that icaritin synergizes with doxorubicin by exacerbating mitophagy and intensifying immunogenic cell death in hepatocellular carcinoma cells—an approach aligning with the concept of “dual-hit” therapies that simultaneously target cancer metabolism and immune evasion. Wang et al. [31], cited 197 times, publish in CANCER LETTERS an overarching review linking immunogenic cell death to clinical outcomes in anticancer chemotherapy, highlighting how heightened immunogenicity can translate into measurable benefits for patient survival. Ishiguro et al. [32], with 144 citations in SCIENCE TRANSLATIONAL MEDICINE, introduce an anti-glypican 3/CD3 bispecific T‑cell-redirecting antibody, demonstrating how immunogenic cell death can dovetail with bispecific immunotherapies to amplify T‑cell-mediated cytotoxicity against solid tumors. Vacchelli et al. [33], cited 125 times in ONCOIMMUNOLOGY, shift attention to toll-like receptor agonists, suggesting that they can serve not only as adjuvants but also as direct inducers of immunostimulatory cell death pathways—an approach later adopted in the design of synthetic immunomodulators. Pinato et al. [2] in JOURNAL FOR IMMUNOTHERAPY OF CANCER, with 112 citations, connect trans-arterial chemoembolization (TACE) to immunogenic cell death, proposing that this locoregional therapy may potentiate systemic immune responses, thereby strengthening the rationale for combining TACE with checkpoint inhibitors. Guo et al. [34], cited 109 times in MOLECULAR CANCER, show that nanoformulations inducing reactive oxygen species can facilitate immunogenetic—or immunogenic—cell death, fueling synergistic chemo-immunotherapy regimens for colorectal cancer and hepatocellular carcinoma alike, while Zhu et al. [35], with 104 citations in CELLULAR ONCOLOGY, describe how oxaliplatin triggers immunogenic cell death and synergizes with immune checkpoint blockade, a concept that broadens the repertoire of combination therapies to include standard chemotherapeutics. Collectively, these works situate immunogenic cell death as a focal point in both basic and translational oncological research, driving innovation in immunotherapy design, combination regimens, and biomarker discovery. Although some of these papers center on broader cancer contexts, each has contributed important frameworks and methodologies that have rapidly been adapted to hepatocellular carcinoma. Their collective emphasis on key molecular mediators—ranging from the PD-1 axis to autophagy, from toll-like receptors to glycosides—reflects a broad-based quest to harness endogenous immune mechanisms against tumor cells. They attest to the increasingly interdisciplinary nature of the field, as collaborations spanning nanotechnology, molecular biology, immunology, and clinical oncology converge on strategies to maximize the immunostimulatory potential of dying cancer cells. These observations set the stage for the Discussion, which contextualises their clinical relevance and addresses remaining challenges.

Discussion

Frontiers and challenges in the field of Immunogenic cell death in hepatocellular carcinoma
Immunogenic cell death in hepatocellular carcinoma (HCC) has rapidly evolved into a focal point of oncological research, yet numerous questions remain unanswered regarding how best to harness it for therapeutic benefit. The heterogeneity of HCC progression and treatment response underscores the need for robust prognostic tools, such as portal venous and hepatic arterial coefficients, to stratify patient outcomes [36]. As shown in Table 3, on the one hand, accumulating evidence indicates that certain molecular signals—such as the release of HMGB1, exposure of calreticulin, and activation of danger-associated pathways—can convert dying tumor cells into potent immunostimulatory agents [37–39]. These signals have been shown to enhance dendritic cell maturation, foster T-cell priming, and ultimately bolster antitumor immunity. However, because HCC typically arises in the context of chronic liver disease, researchers face the added complexity of a highly immunosuppressive tumor microenvironment shaped by underlying cirrhosis, metabolic syndrome, or chronic viral infection. Consequently, the infiltration and functionality of effector T cells may be dampened, limiting the full potential of immunogenic cell death to elicit robust immune responses.Recent interactome-scale studies reveal that hepatitis B virus (HBV) extensively rewires ER-stress, autophagy and innate-immune signalling nodes that also orchestrate ICD, thereby creating virus-specific “bottlenecks” that differ from non-viral HCC [40]. Likewise, a comprehensive protein-interaction atlas of hepatitis C virus (HCV) shows that its structural and non-structural proteins engage host factors that blunt type-I IFN release and antigen cross-presentation, reshaping the ICD landscape in HCV-driven tumors [41]. Recent trials combining anti-PD-1 with oncolytic viruses that induce ICD (NCT05724563) illustrate one practical strategy to counteract this limitation.

A second frontier involves integrating immunogenic cell death in combination regimens. While PD-1/PD-L1 checkpoint blockade has demonstrated efficacy in certain advanced HCC cases, response rates remain suboptimal when administered alone. Emerging findings suggest that combining checkpoint inhibitors with interventions that actively induce immunogenic cell death—such as trans-arterial chemoembolization (TACE), radiofrequency ablation, or the use of selective chemotherapeutic agents—could break resistance barriers and convert “cold” tumors into “hot” ones. At the mechanistic level, these dual or even triple-hit approaches appear to amplify immune-cell infiltration, promote dendritic cell cross-presentation of tumor antigens, and reduce local immunosuppression. Nonetheless, there is still substantial variability in how patients respond to multimodal strategies. This variability underscores the need for multi-omics biomarker panels—integrating transcriptomic ICD signatures (CALR, HMGB1, CXCL10), immune infiltration scores and serum DAMP levels—to predict therapeutic success.
Nanoformulations represent one promising avenue, for instance, pH-responsive liposomes loaded with oxaliplatin have entered phase I evaluation with the explicit endpoint of ICD marker induction, as they can package cytotoxic agents or immunomodulators in a controlled-release format, potentially reducing systemic toxicity and improving immune-cell priming. Yet this approach requires careful design and rigorous evaluation, given the heterogeneity of HCC lesions and the physiological barriers within the liver itself. Ongoing collaborations that bring together expertise in nanotechnology, immunology, and hepatology are essential for refining these delivery vehicles and for establishing standardized criteria to determine their efficacy in clinical trials.In parallel, basic research continues to uncover links between immunogenic cell death and metabolic dysfunction. Oxidative stress, insulin resistance, and obesity have all been implicated not only in promoting HCC but also in influencing how effectively immunogenic cell death can be mounted. Understanding these systemic factors is particularly pressing, as they may either amplify or undermine immune responses, depending on disease stage and individual patient profiles. Indeed, metabolic crosstalk can shape antigen presentation, dendritic cell function, and T-cell exhaustion, thereby complicating efforts to isolate immunogenic cell death as a singular therapeutic trigger. Thus, a key challenge for the field is disentangling these metabolic confounders and pinpointing where interventions like dietary changes, metformin therapy, or lipid-lowering agents could augment immunogenic cell death in HCC. Metformin-mediated AMPK activation has been shown to potentiate ICD in preclinical HCC models, suggesting that metabolic co-interventions could serve as low-cost adjuncts to immunotherapy.
Despite the wave of promising laboratory findings, significant obstacles remain in translating immunogenic cell death-based strategies to routine clinical practice. HCC’s genetic diversity, the multiplicity of etiological factors that drive hepatocarcinogenesis, and the intricacies of immunoediting require tailored approaches that accommodate patient-specific and tumor-specific nuances. Advanced or end-stage disease can further limit the window of opportunity to stimulate an effective immune response. Additionally, standardized guidelines that define and measure immunogenic cell death in vivo remain scarce, complicating the comparison of clinical trial results and the replication of positive outcomes. Overall, the field stands at an inflection point where mechanistic insights must integrate more seamlessly with patient-centered research to clarify which treatment sequences, dosing regimens, and immune biomarkers confer meaningful benefits. By tackling the challenges of tumor immune evasion, refining combination therapies, optimizing drug delivery platforms, and harmonizing clinical trial designs, researchers can propel immunogenic cell death from a promising concept into a cornerstone of HCC therapy.

Future prospects
Looking ahead, future prospects for harnessing immunogenic cell death (ICD) in hepatocellular carcinoma (HCC) will likely revolve around tailoring therapeutic regimens, refining biomarker strategies, and expanding our knowledge of the complex interactions among tumor cells, host immunity, and the liver’s unique microenvironment. One promising direction involves the systematic exploration of combinatorial approaches that merge ICD inducers with targeted immunotherapies, such as novel immune checkpoint modulators or bispecific antibodies [14, 15, 42]. This approach could enhance tumor antigen presentation and effector T-cell priming while simultaneously mitigating the immunosuppressive factors that often accumulate in chronic liver disease. Beyond checkpoint inhibitors, next-generation adoptive cell therapies—including engineered T cells bearing chimeric antigen receptors—may benefit from tumor cells already primed to release immunogenic signals, thus improving infiltration and cytolytic activity. Equally important is the search for robust, reproducible biomarkers that can guide patient selection and monitor therapeutic responses. Efforts to standardize assays for measuring calreticulin exposure, HMGB1 release, or ATP secretion are already underway, yet the next step is to integrate these measurements into routine clinical workflows to help identify patients most likely to respond to ICD-based treatments. As precision oncology continues to evolve, genomic and transcriptomic profiling could aid in pinpointing specific alterations that modulate susceptibility to ICD, paving the way for personalized interventions tailored to each patient’s molecular landscape.
Meanwhile, new insights into how metabolic dysregulation and chronic inflammation intersect with ICD could prompt innovative strategies for targeting modifiable risk factors—such as obesity or viral hepatitis—thereby amplifying the benefits of immune-mediated cell death. On the technological front, advanced drug delivery platforms like pH-sensitive nanoparticles or virus-like particles may improve local concentration of ICD inducers in tumor tissue while minimizing off-target toxicities that can compromise treatment tolerability. Research is also needed to define optimal timing and dosing schedules; for instance, ICD-based regimens could precede or coincide with locoregional therapies such as trans-arterial chemoembolization, thereby transforming standard procedures into immunostimulatory interventions. In addition, a clearer understanding of the interplay between HCC heterogeneity and the immune system is essential, as intratumoral variations in antigen presentation or immune evasion mechanisms might necessitate combination therapies that address multiple pathways simultaneously. Further preclinical studies can leverage organoid and co-culture models to dissect the intricate feedback loops between stromal, immune, and tumor compartments, which often determine whether ICD leads to durable remissions or transient responses. Future clinical trials must prioritize safety and efficacy evaluations—particularly for interventions targeting advanced HCC with vascular involvement—while incorporating immunological endpoints, standardized ICD definitions, and adaptive protocols for early signal detection [43]. Ideally, global collaborations and data-sharing consortia will streamline the integration of ICD-oriented approaches into diverse healthcare settings, especially given the high prevalence of HCC in regions with limited resources. In the coming years, interdisciplinary partnerships that span immunology, nanotechnology, systems biology, and hepatology stand to accelerate progress, ensuring that breakthroughs in ICD research more rapidly translate into tangible patient benefits. The Conclusion distils these insights into actionable recommendations for researchers and clinicians.

Conclusion
This bibliometric study charts the expansion and growing sophistication of ICD research in hepatocellular carcinoma, revealing actionable insights that can guide treatment sequencing, biomarker development, and clinical-trial design. By surveying 568 publications from 2000 to 2024, we traced how scholarly attention initially centered on basic immunological and molecular mechanisms, then shifted toward translational questions encompassing autophagy, checkpoint inhibitors, and combination regimens. Co-authorship analyses revealed robust international engagement, with China and the United States leading overall output and establishing collaborative networks, while the University of California System, Harvard University, and prominent Chinese universities emerged as key institutional hubs. Top-cited articles illuminated diverse breakthroughs, from immunogenic chemotherapy agents to bispecific antibodies, firmly anchoring cell-death pathways at the core of emerging immunotherapeutic strategies. Nevertheless, critical hurdles persist, including the need to align treatment protocols with patient-specific and disease-specific factors, refine biomarkers to predict therapeutic efficacy, and navigate the immunosuppressive microenvironment characteristic of chronic liver disease. Future work should prioritise (i) nanotechnology-based delivery of ICD inducers, (ii) integrated metabolomic–genomic stratification of patients, and (iii) prospective trials that merge ICD-oriented agents with locoregional therapies such as TACE or ablation. Successful execution of these priorities could hasten incorporation of ICD-centric regimens into international treatment guidelines, ultimately improving survival outcomes for patients with advanced HCC.