Hepatocellular carcinoma is the most common primary liver malignancy and a leading cause of cancer death worldwide, particularly in regions where chronic hepatitis B infection is prevalent. The disease often announces itself late, and one of its most ominous signatures is a portal vein tumor thrombus—cancer cells growing into the major vein that carries blood from the gut to the liver. In the classification system used by Chinese hepatologists, such invasion is graded Vp3 or Vp4 depending on whether the thrombus extends into the main portal vein or its contralateral branches. Patients in this category have historically faced grim prospects, because the tumor has already established a highway for spread into the rest of the liver and beyond, and because the compromised liver itself limits how much treatment a patient can tolerate.

In recent years, the backbone of treatment for advanced disease has shifted to systemic combinations: an oral tyrosine kinase inhibitor that starves tumors of their blood supply, paired with an immune checkpoint inhibitor that releases the brakes on T cells. This targeted-immunotherapy approach has improved outcomes compared with older single-agent therapies, but response rates remain modest and many patients progress within months. The question driving the new research was whether adding catheter-based liver treatments on top of these drugs could push survival further. Transarterial chemoembolization delivers chemotherapy directly into the arteries feeding the tumor and then blocks those vessels, concentrating the drug while cutting off nourishment. Hepatic arterial infusion chemotherapy, meanwhile, threads a catheter into the hepatic artery for continuous infusion of high-dose cytotoxic agents, exploiting the fact that liver tumors draw most of their blood from that artery while healthy liver tissue relies on the portal vein.

The study team, led by Qihong Chen and Zhuting Fang of Fujian Cancer Hospital with colleagues at the First Hospital of Putian and collaborating institutions, enrolled 92 patients with Vp3 or Vp4 hepatocellular carcinoma treated at the two centers. Forty-eight patients received the combination of TACE or HAIC with targeted-immunotherapy, while the remainder received targeted-immunotherapy alone. Because patients were not randomly assigned, the researchers used propensity score matching at a 1:2 ratio, a statistical technique that pairs treated and untreated patients with similar baseline characteristics—such as age, liver function, tumor burden, and performance status—to mimic the balance of a randomized experiment. After matching, 48 combination-therapy patients were compared against 31 patients on systemic therapy alone.

The results were striking on the primary measure of tumor response. The objective response rate, assessed with the modified Response Evaluation Criteria in Solid Tumors, which track the viable, contrast-enhancing portion of a tumor rather than its overall size, reached 64.58 percent in the combination group versus 22.58 percent in the systemic-therapy-only group, a difference that was highly statistically significant. In practical terms, nearly two-thirds of patients who received the liver-directed add-on saw their tumors shrink substantially, compared with fewer than a quarter of those on drugs alone. Tumor shrinkage matters not only as a statistical endpoint; in liver cancer, a meaningful reduction in tumor burden can convert an untreatable situation into one where curative-intent options such as resection or ablation become conceivable.

Survival data told a similar story. Median overall survival was 14.2 months in the combination group versus 7.7 months with targeted-immunotherapy alone, corresponding to a hazard ratio of 0.481—meaning the risk of death at any given time was roughly halved. Multivariable Cox regression, which adjusts for multiple factors simultaneously, confirmed that combination therapy was independently associated with a lower risk of death, with a hazard ratio of 0.451. Interestingly, the difference in median progression-free survival—5.8 versus 4.1 months—did not reach statistical significance, a pattern the authors suggest may reflect the relatively small sample size and the fact that progression in these patients is often driven by the biology of portal vein invasion rather than by the treated tumor mass alone.

One of the most clinically useful findings emerged from an exploratory subgroup analysis. Patients whose liver function fell into grade 2 or 3 on the albumin-bilirubin, or ALBI, score—a simple metric that combines serum albumin and bilirubin to quantify hepatic reserve—appeared to derive greater benefit from the combination approach than patients with better-preserved livers. This is somewhat counterintuitive, since a damaged liver might be expected to fare worse under the added insult of arterial chemotherapy and embolization. The authors caution that this observation requires prospective validation, but if confirmed it would help clinicians identify which patients stand to gain the most from an intensified regimen, and it challenges the assumption that only patients with pristine liver function should be offered aggressive locoregional therapy.

Safety, as always in combination oncology, is the counterweight to efficacy. The incidence of grade 3 or worse liver-related adverse events, graded according to the Common Terminology Criteria for Adverse Events, was significantly higher in the combination group—25.00 percent versus 6.45 percent. These events included elevations in liver enzymes and bilirubin, the expected consequences of deliberately injuring tumor-adjacent liver tissue. Crucially, however, all such events were reversible with supportive care, and no treatment-related deaths occurred in the study. The authors frame this as a manageable safety profile, one that demands careful patient selection and vigilant monitoring of hepatic function during treatment, but does not preclude the strategy in patients whose livers can withstand the burden.

The study’s design carries inherent limitations that temper enthusiasm. As a retrospective cohort with a modest sample size, it cannot eliminate selection bias entirely, even with propensity matching; unmeasured differences between patients who received liver-directed therapy and those who did not may persist. The heterogeneity of the regimens—some patients received TACE, others HAIC, and the targeted and immunotherapy agents varied—mirrors real-world practice but complicates interpretation. The authors themselves emphasize that randomized prospective trials are needed before the combination can be considered a standard of care. Still, the magnitude of the survival difference, the consistency of the response-rate benefit, and the corroboration from multivariable analysis make a compelling case that the question deserves definitive testing.

If larger trials confirm these results, the implications for the millions of people living with hepatitis B-related liver cancer could be substantial. The strategy is conceptually elegant: use catheter-based arterial therapies to deliver a concentrated cytotoxic blow to the tumor and its portal vein thrombus, while systemic targeted-immunotherapy patrols for micrometastatic disease and, perhaps, is potentiated by the release of tumor antigens caused by local treatment. The Fujian study adds to a small but growing body of evidence that the era of purely systemic treatment for advanced hepatocellular carcinoma may be giving way to a more integrated model, in which the interventional radiologist’s catheter and the medical oncologist’s prescriptions work in concert. For patients facing a diagnosis that once carried a prognosis measured in months, that convergence may soon translate into years.

Subject of Research: Combining transarterial therapies with targeted-immunotherapy for advanced hepatocellular carcinoma with portal vein tumor thrombus

Article Title: Efficacy and safety of TACE/HAIC combined with targeted-immunotherapy versus targeted-immunotherapy alone in Vp3-4 hepatocellular carcinoma: a propensity score-matched retrospective cohort study based on two-center data

Article References: Efficacy and safety of TACE/HAIC combined with targeted-immunotherapy versus targeted-immunotherapy alone in Vp3-4 hepatocellular carcinoma: a propensity score-matched retrospective cohort study based on two-center data. (n.d.). https://doi.org/10.1186/s12885-026-17061-4

Image Credits: AI Generated

DOI: 10.1186/s12885-026-17061-4

Keywords: hepatocellular carcinoma, portal vein tumor thrombus, TACE, HAIC, targeted-immunotherapy, overall survival, propensity score matching, liver cancer, combination therapy, adverse events, ALBI grade, BMC Cancer

Conversion therapy, sometimes called downstaging therapy, refers to the use of systemic drugs, local regional treatments, or both, to shrink initially unresectable tumors until they become candidates for curative surgery. The concept has gained momentum in recent years as systemic treatments have improved dramatically. Combinations of anti-angiogenic targeted drugs and immune checkpoint inhibitors now achieve objective response rates of around 30 percent in advanced or unresectable hepatocellular carcinoma, while local therapies such as transarterial chemoembolization (TACE), hepatic artery infusion chemotherapy (HAIC), and radiation therapy have become more effective at reducing tumor volume and controlling tumor thrombus within blood vessels. When these approaches succeed, patients who once had no surgical option can undergo resection, and studies suggest their post-surgical survival can approach that of patients whose tumors were resectable from the start.

To understand how this evolving paradigm is actually being applied, a team led by investigators from the National Cancer Center in Beijing and the China Liver Cancer Study Group Young Investigators conducted a structured survey between January and July 2024. The researchers distributed questionnaires to physicians meeting strict criteria: they had to work at a tertiary hospital, practice in hepatobiliary surgery or interventional radiology, hold the rank of associate chief physician or above, see at least five new hepatocellular carcinoma patients per month, and serve as primary decision-makers for conversion therapy. Ultimately, 120 valid responses were collected from 79 tertiary hospitals across 20 provinces. Nearly 70 percent of respondents were hepatobiliary surgeons and the remainder were interventional radiologists, reflecting the two specialties that dominate conversion therapy decision-making in China’s disease-centered, surgery-led multidisciplinary model.

The headline finding is striking: physicians reported that approximately 51 percent of newly diagnosed patients with stage Ib to IIIa disease, according to the China Liver Cancer Staging (CNLC) system, were selected for conversion or downstaging treatment with the goal of eventual resection. The proportion was highest among patients with stage IIb and IIIa tumors, of whom 52 percent and 59 percent respectively received such treatment. In other words, more than half of newly diagnosed patients in these intermediate stages are now being routed through a treatment pathway designed to convert an impossible operation into a possible one. This represents a profound shift from a decade ago, when most of these patients would have gone directly to palliative local or systemic therapy without any surgical ambition.

Which patients do physicians choose for this aggressive approach? The survey identified three dominant factors. Portal vein tumor thrombus (PVTT)—the invasion of tumor into the main blood vessel draining the liver—was considered by 97 percent of respondents, making it the most widely weighed criterion. Future liver remnant volume, the amount of healthy liver that would remain after resection, and Child–Pugh liver function classification were each cited by 90 percent. Tumor number followed at 89 percent, with extrahepatic metastasis and tumor size each at 88 percent. When physicians rated the importance of each factor on a seven-point scale, extrahepatic metastasis and portal vein tumor thrombus received the highest weights, with 82 percent and 78 percent of relevant respondents scoring them six or above. The typical candidate for conversion therapy, according to the respondents, had Child–Pugh A liver function or well-preserved B7 function, a tumor larger than five centimeters, good performance status, and early or moderate portal vein tumor thrombus.

The prominence of portal vein tumor thrombus reveals a genuine philosophical evolution in the field. Under the Barcelona Clinic Liver Cancer (BCLC) staging system, used widely in Europe and the United States, hepatocellular carcinoma with portal vein invasion is classified as advanced stage C, and systemic therapy is recommended as the only option. Japanese guidelines take a middle path, recommending surgery when thrombus has not invaded first-order portal vein branches. Chinese guidelines classify vascular invasion as stage IIIa and list TACE with or without systemic therapy as the primary treatment, followed by surgery. Yet 72 percent of surveyed physicians considered patients with Vp1/2 thrombus—where tumor invasion remains limited—suitable for conversion therapy, reflecting what the authors describe as a shift from a narrow to a broad concept of conversion intent. The rationale is twofold: modern drug combinations can shrink both the tumor and the thrombus, facilitating complete resection, and the treatment period itself helps identify biologically aggressive tumors that would recur quickly after surgery, sparing those patients a futile operation.

When it comes to the regimens themselves, the survey found overwhelming preference for combination therapy. Approximately 73 percent of patients received a combination of local treatment with targeted therapy and immunotherapy. Within this group, 29 percent received targeted plus immunotherapy with TACE, 26 percent with HAIC, and 18 percent with both local modalities together. Only about 10 percent of physicians used systemic therapy alone. Interventional radiologists were significantly more likely than surgeons to favor quadruple combinations including both TACE and HAIC, while surgeons more often selected systemic therapy alone. The biological logic of these combinations is compelling: anti-angiogenic drugs inhibit the new vessel formation that TACE can paradoxically stimulate, while TACE itself increases expression of immune-suppressive molecules such as CTLA-4 and PD-L1, which immune checkpoint inhibitors then block, restoring anti-tumor immunity. A recent meta-analysis covering 2007 to 2024 reported conversion rates of 5 to 28 percent for systemic therapy alone, 13 to 33 percent for combined local and systemic therapy, and peaks around 35 percent for regimens combining lenvatinib, PD-1 inhibitors, and local treatment.

Drug selection showed a clear winner. Lenvatinib combined with immunotherapy was the preferred systemic backbone for 64 percent of physicians, with 49 percent using the original formulation and 13 percent using generics. The next most popular regimens—bevacizumab biosimilar with sintilimab, and bevacizumab with atezolizumab—trailed far behind at around 11 percent. Physicians explained their choices through a hierarchy of priorities: a higher objective response rate was the foremost consideration for 83 percent, followed by rapid onset of response at 68 percent, adherence to guidelines and consensus documents at 63 percent, and lower tumor progression rate at 58 percent. Lenvatinib-based regimens scored well across efficacy, safety, and practical metrics, including lower bleeding risk, shorter preoperative drug discontinuation times, and easier dose adjustment—considerations that matter enormously when the endpoint is not merely tumor control but a safe operation.

What defines success, and what happens after it? Physicians ranked R0 resectability—the ability to remove all visible tumor with clear margins—as the most important criterion for successful conversion, selected by 96 percent and weighted most heavily. Tumor thrombus regression, adequate future liver remnant volume, achievement of complete or partial radiological response, and tumor stability for more than two months followed. The survey’s estimated overall conversion success rate was approximately 32 percent, but the figure fell sharply with disease stage: 57 percent for stage Ib patients, 42 percent for stage IIa, 35 percent for stage IIb, 28 percent for stage IIIa, and just 15 percent for stage IIIb, where extrahepatic metastases make radical surgery far harder to achieve. Among patients who converted successfully, about 57 percent went on to surgery, and 79 percent of those surgical patients received postoperative adjuvant therapy, most commonly systemic treatment with targeted and immunotherapy combinations.

The authors are candid about the limitations of their work. All surveyed hospitals were tertiary referral centers, so the findings may not generalize to community hospitals. The conversion success rates reflect physician estimates rather than audited patient-level data, and the anonymous cross-sectional design precluded assessing test–retest reliability or comparing respondents with non-respondents. Still, the survey’s value lies in mapping real-world clinical attitudes at a moment when the evidence base consists largely of retrospective studies and small single-arm trials, with randomized controlled data still scarce. By documenting that over half of newly diagnosed intermediate-stage patients in China are now considered candidates for conversion therapy, and by identifying the criteria and regimens that dominate practice, the study provides a foundation for the multicenter collaboration and standardized protocols that the authors say are needed next. For a disease that kills more than 300,000 people a year in China alone, turning initially hopeless diagnoses into curative operations is a goal worth pursuing with both enthusiasm and rigor.

Subject of Research: Physician perceptions and clinical practice of conversion and downstaging therapy for hepatocellular carcinoma in China

Article Title: Physicians’ perceptions of HCC conversion/downstaging therapy: a nationwide survey among tertiary hospital physicians in China

Article References: Bi, X., Liang, X., Tan, G., Zhao, H.-T., Huang, T., Zhao, M., Chen, J., Zhu, X.-D., Xue, J., Sun, H.-C., Cai, J., & China Liver Cancer Study Group Young Investigators(CLEAP) (2026). Physicians’ perceptions of HCC conversion/downstaging therapy: a nationwide survey among tertiary hospital physicians in China. Holistic Integrative Oncology, 5(1), Article 37. https://doi.org/10.1007/s44178-026-00256-x

Image Credits: AI Generated

DOI: 10.1007/s44178-026-00256-x

Keywords: hepatocellular carcinoma, conversion therapy, downstaging, portal vein tumor thrombus, liver cancer, lenvatinib, immunotherapy, TACE, HAIC, surgical resection, China, nationwide survey

Hepatocellular carcinoma, the most common form of primary liver cancer, accounts for nearly 90 percent of liver cancer cases worldwide. Because the disease rarely produces symptoms in its early stages, most patients are diagnosed when the tumor is too advanced for surgical resection, the treatment that offers the greatest survival benefit. Conversion therapy has emerged as a strategy to change that prognosis. By combining locoregional treatments such as transarterial chemoembolization (TACE) or hepatic arterial infusion chemotherapy (HAIC) with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), clinicians aim to shrink tumors enough to make radical surgery possible. The approach has transformed the treatment landscape, but responses vary dramatically between patients, and predicting who will benefit remains one of the field’s most pressing challenges.

The retrospective study, conducted at the First Affiliated Hospital of Shandong First Medical University, screened 834 patients with primary hepatocellular carcinoma and identified 63 who met the criteria for analysis. Most were male, the majority carried hepatitis B, and more than three quarters had cirrhosis. All received at least two treatment modalities drawn from the conversion therapy arsenal: TACE or HAIC to cut off the tumor’s blood supply and deliver chemotherapy directly, TKIs such as sorafenib or lenvatinib to target tumor signaling pathways, and ICIs such as camrelizumab or sintilimab to unleash anti-tumor immune responses. The results were clinically encouraging. Two patients achieved a complete response and 26 a partial response, yielding an objective response rate of 44.4 percent and a disease control rate of 90.1 percent. Twenty-four patients, or 38.1 percent, were successfully converted to a resectable state, and every one of them underwent radical R0 resection with clear surgical margins.

But the study’s most provocative findings came from the laboratory rather than the clinic. The researchers collected formalin-fixed paraffin-embedded tumor tissue from 15 patients who underwent resection after triple conversion therapy and stratified them by pathological response. Major pathological responders, defined as having more than 50 percent tumor necrosis, formed one group; minor responders, with 50 percent or less necrosis, formed the other. Genomic DNA was extracted and the V3-V4 region of the 16S rRNA gene was amplified and sequenced on an Illumina platform, with amplicon sequence variants clustered using the DADA2 algorithm and taxonomy assigned against the SILVA database. The interval between the last treatment dose and surgery was statistically indistinguishable between the two groups, ruling out differences in treatment withdrawal time as a confounding factor.

The sequencing data revealed a striking divergence. Tumors from minor responders harbored significantly higher microbial alpha diversity, measured across the Chao1, Observed-species, Shannon, and Simpson indices, and their overall community composition differed on principal coordinate analysis of weighted UniFrac distances. At the phylum level, minor responders were enriched in Acidobacteriota, Chloroflexi, Planctomycetota, Gemmatimonadota, and Verrucomicrobiota, while major responders were dominated by Proteobacteria and Bacteroidetes. At the genus level, Halomonas and Arthrobacter stood out in minor responders, whereas Escherichia-Shigella and Limosilactobacillus were markedly more abundant in major responders. Linear Discriminant Analysis Effect Size confirmed these taxa as robust biomarkers, with LDA scores exceeding 3.0.

Functional prediction using PICRUSt2 added a metabolic dimension to the story. Microbiota in minor responders showed enhanced pathways related to methane metabolism, terpenoid backbone biosynthesis, and cofactor and vitamin metabolism, while major responders displayed elevated fatty acid biosynthesis and general functional activity. These metabolic signatures suggest that intratumoral bacteria may influence how tumors process nutrients and metabolites during therapy, potentially modulating the microenvironment in ways that either support or undermine treatment. Escherichia-Shigella, for example, is known to produce short-chain fatty acids with immune-regulatory and anti-tumor properties, while Limosilactobacillus can influence dendritic cell differentiation and thereby shape immune responses.

The most visually compelling evidence came from RNAscope in situ hybridization combined with immunofluorescence staining, which allowed the researchers to see where Halomonas bacteria and CD8-positive T cells actually resided within tumor sections. In major responders, Halomonas signals were sparse while CD8-positive T cells infiltrated the tumor abundantly. In minor responders, the pattern reversed: dense Halomonas colonization coexisted with conspicuously few T cells. The merged fluorescence images revealed a mutually exclusive spatial relationship, with bacteria-rich regions largely devoid of immune cell infiltration. The authors propose that extensive Halomonas colonization may promote immune exclusion, blunting the effectiveness of immune checkpoint inhibitors. One plausible mechanism involves L-arginine, a metabolite essential for T cell activation and proliferation that has been reported to correlate negatively with Halomonas abundance; bacterial consumption of this amino acid could starve T cells of a resource they need to function.

The findings fit into a broader rethinking of tumor biology. Long considered sterile, tumors are now known to harbor microbiota across many cancer types, and these resident microbes can influence everything from tumorigenesis to therapeutic response. Intratumoral Bifidobacterium, for instance, has been shown to stimulate STING signaling in dendritic cells and amplify CD47-based immunotherapy in preclinical models. Prior studies have also linked intratumoral microbial signatures in hepatocellular carcinoma to patient prognosis after surgery. What sets the new work apart is its focus on conversion therapy, an area where intratumoral microbiota had been almost entirely unexplored, and its demonstration that microbial profiles track with pathological response rather than merely with tumor presence.

Notably, the study found no significant differences in microbiota composition between tumor tissue and adjacent non-tumor tissue in patients who underwent direct surgery, nor between direct surgery patients and those who received conversion therapy. The authors attribute this to the small sample size of those comparisons and caution that it limits interpretation. The study also carries other constraints: the cohort was small and relatively homogeneous, the conversion therapy protocols varied between patients, and the retrospective design precludes causal inference. The researchers are now conducting a prospective trial of cardunolizumab and lenvatinib combined with TACE in patients with initially unresectable hepatocellular carcinoma, which may provide the validation needed to move microbial biomarkers toward clinical use.

Even with those caveats, the implications are considerable. If intratumoral microbiota profiles can be measured before or early in treatment, they could help clinicians identify which patients are likely to achieve major pathological response and tailor conversion therapy accordingly. They might also point toward interventions, such as modulating specific bacterial populations or their metabolic products, that could sensitize resistant tumors to immunotherapy. For a disease that remains among the deadliest malignancies worldwide, the idea that answers may lie partly within the tumors themselves, in the microscopic ecosystems that colonize them, represents an intriguing new frontier. The study is the first to demonstrate the involvement of intratumoral microbiota in the response of unresectable hepatocellular carcinoma to conversion therapy, and it provides preliminary but tangible evidence that these microbial communities could serve as prognostic biomarkers for predicting treatment outcomes.

Subject of Research: Intratumoral microbiota composition and its association with pathological response to conversion therapy in unresectable hepatocellular carcinoma

Article Title: Therapeutic response-driven discrepancies in intratumoral microbiota composition of hepatocellular carcinoma following conversion therapy

Article References: Ma, L., Xu, J., Wang, F., Xu, Z., Liu, F., Li, T., Liu, X., Yin, B., Xiao, J., Tian, H., Li, Z., Liu, C., & Liang, J. (2026). Therapeutic response-driven discrepancies in intratumoral microbiota composition of hepatocellular carcinoma following conversion therapy. Holistic Integrative Oncology, 5(1), Article 55. https://doi.org/10.1007/s44178-026-00275-8

Image Credits: AI Generated

DOI: 10.1007/s44178-026-00275-8

Keywords: hepatocellular carcinoma, intratumoral microbiota, conversion therapy, immune checkpoint inhibitors, tyrosine kinase inhibitors, TACE, HAIC, 16S rRNA sequencing, Halomonas, CD8 T cells, pathological response, tumor microenvironment