4.1 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.

Fig. 1

Keyword co-occurrence network

Fig. 2

Overlay visualization of keyword co-occurrence by year

Fig. 3

Treemap of keyword frequency

4.2 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.

Fig. 4

Word cloud of high-frequency terms

Fig. 5

Country co-authorship network

Fig. 6

Country collaboration map

4.3 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.

4.4 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.

4.5 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.

Fig. 7

Author co-authorship network

Fig. 8

Authors’ production over time

Fig. 9

Most relevant affiliations

Fig. 10

Institutional co-authorship network

Fig. 11

Trend of published articles over time

4.6 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.

Table 1 Annual publication volume and year-over‐year changes4.7 Analysis of the ten most highly cited documents

As shown in Table 2 [2, 27,28,29,30,31,32,33,34,35], 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.

Table 2 Top ten most cited articles on ICD in HCC