Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography: A Potential Imaging Biomarker for Predicting Response to Combination Immunotherapy in Hepatocellular Carcinoma.

FDG-PET-Positive HCC and Glucose Metabolism: Its Association with Immunosuppressive Immune Microenvironments
FDG reflects the glucose metabolic activity of tumors. Tumors with high FDG uptake have enhanced glycolytic activity (the Warburg effect) and accumulate lactate, a metabolic byproduct. This tumor-derived lactate promotes the recruitment and function of immunosuppressive cells such as regulatory T cells (Tregs) [12–14], myeloid-derived suppressor cells (MDSCs) [15], and tumor-associated macrophage (TAM) [16], thereby forming an immunosuppressive tumor immune microenvironment (TIME) (Fig. 1).
Recently, a novel molecular classification of HCC has been proposed based on metabolic reprogramming – a hallmark of cancer biology [17]. This classification divides tumors into two major groups: those retaining hepatocyte-specific metabolic functions (e.g., bile acid, fatty acid, and amino acid metabolism) and those that lose such functions and show enhanced glycolysis. Notably, the latter tend to be poorly differentiated (Hoshida S1/2) and exhibit high expression of glucose transporters, increased lactate production, and high FDG uptake.
This glycolysis-enhanced phenotype is also observed in gastric, lung, breast, and ovarian cancers [12, 18]. In this metabolic state, glucose is rapidly converted to fructose-6-phosphate and subsequently to pyruvate and lactate, even under aerobic conditions. Thus, FDG/PET-CT captures high glucose uptake in these tumors [13]. Lactate accumulation and hypoxia, both products of enhanced glycolysis, create an acidic TIME. This environment impairs cluster of differentiation 8 positive T cell (CD8+ T cell) function, induces programmed cell death-1 (PD-1) expression on Tregs, and promotes M2 macrophage polarization – further reinforcing an immunosuppressive TIME [14, 19]. Indeed, high Treg infiltration is associated with enhanced glycolysis in HCC [20].

Immune Microenvironment of FDG-PET-Positive HCC Is Actually an “Inflamed” Hot Tumor
As described, FDG-PET-positive HCCs are embedded in an immunosuppressive TIME enriched with Tregs, MDSCs, and TAMs. Lactate enhances the immunosuppressive functions of these myeloid cells through distinct molecular pathways. Specifically, lactate activates MDSCs via the GPR81-HIF-1α-STAT3 axis, suppressing IFNγ+ T cells, while also promoting M2 polarization of TAMs through HIF-1α-dependent induction of arginase 1 and vascular endothelial growth factor (VEGF), thereby facilitating tumor growth and angiogenesis [15, 16] (Fig. 1). However, recent translational studies show that these tumors are not “immune cold,” but rather “immune hot,” with significant CD8+ T-cell infiltration and high PD-L1 expression [21, 22]. This indicates that FDG-PET-positive HCCs tend to have an inflamed TIME. It is assumed that within the immune subclass of HCC [23], these tumors belong to the “immune-exhausted” subtype (Fig. 2). Therefore, if this TIME can be changed from immunosuppressive to immunoresponsive through anti-VEGF or anti-CTLA-4 antibodies, the tumors will become responsive to immune checkpoint inhibitors (ICIs).

Therapeutic Efficacy of Immunotherapy for FDG-PET-Positive HCC
Recently, case reports and retrospective studies have shown the efficacy of immunotherapy for FDG-PET-positive HCC. Uchida et al. [24] reported a case of advanced HCC treated with atezolizumab plus bevacizumab (Atezo/Bev), achieving complete metabolic response on FDG-PET. In 20 patients with unresectable HCC, the tumor-to-liver ratio measured by pretreatment FDG-PET/CT was shown to be a useful predictor of the likelihood of conversion surgery and prognosis following lenvatinib (LEN) plus PD-1 inhibitor therapy [25]. Patients with a high tumor-to-liver ratio had a higher conversion surgery rate and better PFS and OS. Wang et al. [26] reported that FDG-PET is a useful imaging biomarker with high accuracy for predicting pathological response and prognosis in 28 patients with unresectable HCC who undergo conversion therapy after treatment with LEN plus PD-1 inhibitors. A multicenter retrospective study by Lee et al. [27] indicated that pretreatment PET metabolic markers (e.g., TLG, SUVmax) may serve as prognostic factors for Atezo/Bev efficacy. In addition, a multicenter proof-of-concept study showed that in seven PET-positive intermediate-stage HCC cases, a combination of Atezo/Bev followed sequentially by LEN-TACE, conversion therapy using surgical resection, or ablation led to drug-free and cancer-free status very quickly [28].
In our own cohort of 23 FDG-PET-positive HCC cases, all showed at least an initial response to Atezo/Bev. However, in 9 patients, tumor marker re-elevation such as PIVKA-II re-elevation or elevation of previously negative AFP-L3 indicated waning efficacy. Adding LEN-TACE at this stage led to cancer-free outcomes (unpublished data). Interestingly, LEN is also effective against poorly differentiated or FDG-PET-positive HCC [29, 30], suggesting a potential treatment strategy of sequencing Atezo/Bev and LEN-TACE.
VEGF inhibition by bevacizumab or LEN may enhance the effect of PD-L1 antibodies by ameliorating the immunosuppressive TIME. Furthermore, a report showed that 21 cases of FDG-PET-positive HCC responded well to durvalumab plus tremelimumab (Durva/Treme) [31]. The reason for an ICI + ICI regimen without VEGF inhibition can work in an immune-exhausted TIME which may lie in anti-CTLA-4 antibodies’ ability to deplete Tregs [32–34], thereby increasing CD8+ T cells (increase the relative CD8+/Treg ratio) and boosting the efficacy of anti-PD-1/L1 antibodies. This mechanism is believed to be shared by both nivolumab + ipilimumab and Durva/Treme.

Clinical Significance and Future Perspectives of FDG-PET-Positive HCC
Reports suggesting the efficacy of combination immunotherapy for FDG-PET-positive HCC are accumulating, and FDG-PET is emerging as a promising imaging biomarker for predicting favorable treatment response. However, these findings are still preliminary and require confirmation in future prospective studies.
At present, we could only state that “FDG-PET-positive HCC is likely to respond to combination immunotherapy based on retrospective and exploratory clinical observations.” In fact, there are FDG-PET-negative HCCs that also respond to ICI plus anti-VEGF/TKI or ICI plus anti-CTLA-4 therapy, especially in the other inflamed tumor such as “active immune subclass or immune-like subclass” (Fig. 2). Therefore, treatment decision-making cannot be changed based on FDG-PET status. In addition, FDG-PET positivity reflects enhanced glycolytic metabolism and may not directly correspond to immunological responsiveness. Recent multi-omics studies [35, 36] have shown that some HCCs classified as “immune-exhausted” or Treg-rich, despite being inflamed, may not respond favorably to combination immunotherapy. Cappuyns et al. [35] analyzed 422 bulk RNA-seq and 31 single-cell RNA-seq data from advanced HCC patients treated with systemic therapies including Atezo/Bev and identified two molecular subgroups associated with clinical benefit: an immune-competent subgroup and an angiogenesis-driven subgroup. The latter exhibits molecular features including frequent TP53 mutations, upregulated MYC signaling, and high chromosomal instability, and is characterized by reduced infiltration of CD8+ effector T cells and enrichment of NRP1-negative endothelial cells. Furthermore, Myojin et al. [36] performed integrative transcriptomic analyses on 28 HCC tumor samples subjected to Durva/Treme, revealing that nonresponders exhibited higher Treg accumulation, particularly in immune cell-enriched neighborhoods, along with increased expression of PD-1 and ICOS. These findings were validated in orthotopic transplantation models (Hep55.1c and RIL175) that received anti-PD-L1 and anti-CTLA-4 antibodies. Although these studies did not assess FDG-PET imaging, their findings suggest that tumor glycolysis-associated immunosuppressive environments may not uniformly predict treatment benefit from combination immunotherapy. Nonetheless, therapeutic combinations incorporating PD-1 inhibitors with agents that target immunosuppressive elements of the tumor microenvironment, such as anti-VEGF therapies (e.g., bevacizumab, LEN) or anti-CTLA-4 antibodies, may confer clinical benefit in a subset of PET-positive, glycolysis-driven HCC cases.

FDG-PET as a Potential Imaging Biomarker for Predicting Response to Combination Immunotherapy in HCC
In real-world clinical practice, reliable biomarkers to predict treatment response to combination immunotherapy in HCC remain lacking, posing a significant challenge for clinical decision-making. Although FDG-PET is not a definitive predictor of therapeutic efficacy, it may serve as a surrogate marker to noninvasively identify inflamed subtypes of HCC, even those characterized by immunosuppressive tumor microenvironments. Given that combination immunotherapies, such as Atezo/Bev and IO plus anti-CTLA-4 antibodies (e.g., Dueva/Treme or Nivo/Ipi), can reprogram immunosuppressive microenvironments into immune-reactive states, partly through VEGF blockade or Treg depletion, it may be clinically meaningful to stratify patients based on inflamed tumor phenotypes using FDG-PET. In that sense, FDG-PET may serve as a potential imaging biomarker for identifying HCCs that are more likely to respond to combination immunotherapy, at least in a subset of FDG-PET-positive HCC cases that exhibit favorable therapeutic responses. However, further studies are warranted to better understand and validate this hypothesis.

Statement of Ethics
No statement is needed because this study was based exclusively on published data.

Conflict of Interest Statement
Masatoshi Kudo reports lectures from Chugai, Eisai, and AstraZeneca; grants from Otsuka, Taiho, Chugai, GE Healthcare, and Eisai; advisory consulting from Chugai, Roche, Eisai, and AstraZeneca. Masatoshi Kudo is the Editor-in-Chief of Liver Cancer.

Funding Sources
There was no funding for this editorial.

Author Contributions
Masatoshi Kudo conceived, wrote, and approved the final manuscript.