Liver cancer is usually diagnosed at an advanced stage and is the third most common cause of cancer-related death worldwide. In addition to the lack of effective treatment options, resistance to therapeutic drugs is a major clinical challenge. The gut microbiota has recently been recognized as one of the key factors regulating host health. The microbiota and its metabolites can directly or indirectly regulate gene expression in the liver, leading to gut-liver axis dysregulation, which is closely related to liver cancer occurrence and the treatment response. Gut microbiota disturbance may participate in tumor progression and drug resistance through metabolite production, gene transfer, immune regulation, and other mechanisms. However, systematic reviews on the role of the gut microbiota in drug resistance in liver cancer are lacking. Herein, we review the relationships between the gut microbiota and the occurrence and drug resistance of hepatocellular carcinoma, summarize the emerging mechanisms underlying gut microbiota-mediated drug resistance, and propose new personalized treatment options to overcome this resistance.

Lenvatinib (LEN)-treated patients with hepatocellular carcinoma (HCC) are frequently accompanied by skeletal muscle loss, which is correlated with poor prognosis. Interactions between tumor and skeletal muscle may play a role in patient prognosis and tumor progression. We here demonstrated that LEN hindered proliferation and differentiation of the mouse myoblast cell line, C2C12 cells, by blocking the ERK1/2 and AKT signaling pathways. Transcriptome analysis revealed that multiple EGF-like domains 6 (Megf6) was upregulated in LEN-treated C2C12 cells. Furthermore, we observed that compared with normal adjacent tissues, MEGF6 was highly expressed in HCC tumor tissues according to the TCGA database, which suggested MEGF6-mediated interaction between tumor and skeletal muscle. The Megf6 knockdown restored the differentiation inhibition caused by LEN and ERK1/2 inhibitors; however, it had no significant impact on proliferation. Regarding mechanism, LEN increased Megf6 expression through the ERK1/2 signaling pathway, thereby resulting in myostatin expression elevation and myosin heavy chain protein expression repression. Furthermore, MEGF6 in LEN-treated C2C12 cell medium promoted tumor cell proliferation and impaired C2C12 cell differentiation when cultured with LEN-treated tumor cell medium. Clinically, patients who were accompanied by muscle mass loss and increased MEGF6 serum levels had shorter progression-free survival than those who were accompanied by muscle mass loss but no increased MEGF6 serum levels before and after LEN treatment. In conclusion, MEGF6 produced from muscle and tumor cells could impair muscle differentiation and enhance tumor proliferation. Therefore, MEGF6 is worth further investigating as a target for improving the prognosis of LEN-treated patients with HCC.

Tumour-associated macrophages (TAMs) contribute to hepatocellular carcinoma (HCC) progression. However, while the pro-tumour and immunosuppressive roles of lipid-loaded macrophages are well established, the mechanisms by which lipid metabolism enhances the tumour-promoting effects of TAMs remain unclear.

Single-cell RNA sequencing was performed on mouse and human HCC tumour samples to elucidate the landscape of HCC TAMs. Macrophages were stimulated with various long-chain unsaturated fatty acids (UFAs) to assess immunosuppressive molecule expression in vitro. Additionally, in vivo and in vitro studies were conducted using mice with macrophage-specific deficiencies in fatty acid-binding protein 5 (FABP5) or peroxisome proliferator-activated receptor γ (PPARγ).

Single-cell RNA sequencing identified a subpopulation of FABP5+ lipid-loaded TAMs characterized by enhanced immune checkpoint blocker ligands and immunosuppressive molecules in an oncogene-mutant HCC mouse model and human HCC tumours. Mechanistically, long-chain UFAs released by tumour cells activate PPARγ via FABP5, resulting in immunosuppressive properties in TAMs. FABP5 deficiency in macrophages decreases immunosuppressive molecule expression, enhances T cell-dependent antitumour immunity, diminishes HCC growth, and improves immunotherapy efficacy.

This study demonstrates that UFAs promote tumourigenesis by enhancing the immunosuppressive tumour microenvironment via FABP5-PPARγ signalling and provides a proof-of-concept for targeting this pathway to improve the efficacy of tumour immunotherapy.

Despite the role of tumour-associated macrophages (TAMs) in promoting tumour progression being well established, the mechanisms by which lipid metabolism enhances the tumour-promoting effects of TAMs remain unclear. Our study reveals that FABP5-mediated unsaturated fatty acid metabolism in TAMs is crucial for modulating antitumour T-cell immunity and influencing the efficacy of immunotherapy. This finding provides novel insights into the immunomodulatory roles of FABP5+ lipid-loaded TAMs in hepatocellular carcinoma and suggests that targeting FABP5 could offer a new approach to liver cancer treatment.

Locoregional therapies play a fundamental role in the treatment of patients with early and intermediate and locally advanced hepatocellular carcinomas. With encouraging recent advances in immunotherapy-based systemic therapies, locoregional therapies are being both promoted and challenged by new systemic therapy options. Combined locoregional and systemic therapies might enhance treatment outcomes compared with either option alone. This Series paper summarises the existing data on locoregional and systemic therapies for hepatocellular carcinoma, and discusses evidence from studies investigating their combination with a focus on their synergistic efficacy and safety.

Over the past years, there has been a remarkable advance in the systemic treatment options for advanced HCC. The overall survival has gradually increased over time, with larger benefits for patients with sensitive tumors and preserved liver function, the latter being an essential condition for the delivery of sequential lines of treatment and optimization of clinical outcomes. With the approval of new first-line agents and the introduction of immune checkpoint inhibitor-based therapies, the treatment landscape of advanced HCC is becoming wider than ever. Atezolizumab plus bevacizumab and, more recently, durvalumab plus tremelimumab have entered the clinical practice and are the current standard of care for treatment-naïve patients, surpassing sorafenib and lenvatinib monopoly. As no head-to-head comparisons are available among all the first-line treatment options, the recommendation for the most appropriate choice and sequence is patient-driven and integrates efficacy data with clinical comorbidities, background liver disease, and the safety profile of available drugs. In addition, predictive biomarkers for successful patients' stratification are yet to be available and constitute the focus of ongoing research. The treatment algorithm is likely to become even more complex since systemic therapeutic approaches are now being translated into earlier stages of the disease, with an impact on the evolution of the sequential treatment of patients with HCC.

The risk of HCC is twice as high in diabetic patients compared to non-diabetic ones, suggesting that diabetes advances carcinogenesis in the liver through a variety of mechanisms. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown to improve liver outcomes, emerging as promising agents to treat hepatocellular carcinoma (HCC) in patients with type 2 diabetes mellitus (T2DM).

We searched PubMed and Scopus databases for articles presenting an association between SGLT2is and HCC to explore the putative mechanisms of action underlying the anti-proliferative activity of SGLT2is.

A total of 24 articles were selected for inclusion, of which 14 were preclinical and 10 were clinical. Preclinical studies were mainly focused on canagliflozin, used alone or in combination with other drugs.

Overall, canagliflozin had a negative effect on HCC cell proliferation by interfering with glucose-dependent and independent metabolic pathways, negatively impacting angiogenesis, and inducing apoptosis in in-vitro cell models. In-vivo, a protective effect on hepatic steatosis and fibrosis and HCC development has been reported. Human studies showed a lower risk of developing HCC in patients on SGLT2is. However, this is supported by retrospective cohort studies. Clinical trials are needed to confirm the causal relationship between SGLT2i administration and HCC development.

Tyrosine kinase inhibitors (TKIs) are such as sorafenib the first-line therapeutic drugs for patients with advanced hepatocellular carcinoma. However, patients with TKI-resistant advanced liver cancer are insensitive to TKI treatment, resulting in limited survival benefits. This paper comprehensively reviewed the mechanisms underlying TKI resistance in hepatocytes, investigating activation of tumor signaling pathways, epigenetic regulation, tumor microenvironment, and metabolic reprogramming. Based on resistance mechanisms, it also reviews preclinical and clinical studies of drug resistance strategies and summarizes targeted therapy combined with immunotherapy currently in investigational clinical trials. Understanding the interactions and clinical studies of these resistance mechanisms offers new hope for improving and prolonging patient survival.

To provide a reference for hepatocellular carcinoma (HCC) clinical trials, we analyzed HCC clinical trials and therapeutic targets.

Using the Informa database, we analyzed the global and China HCC clinical trials. We then explored TACE, Apatinib, and emerging strategies (CAR T/NK). Additionally, we analyzed the oncogenic biomarkers and therapeutic targets. We conducted a joint analysis of therapeutic target safety using HPA-RNA, HPA-Proteins, and GTEx-RNA datasets. Finally, we analyzed the specificity and prospects of therapeutic targets using HPA pathology data and CPTAC data.

HCC clinical trials have developed rapidly over the past decade but have now reached a bottleneck, with most breakthroughs focusing on combination therapies. China and the USA dominate in the number of trials. TACE combined with systemic therapy has become an effective treatment strategy for intermediate to advanced HCC. Apatinib and TACE combined with systemic therapy are characteristic of China, while the latter is also mainly conducted in Japan and the USA. Currently, targeted immune therapies dominate the field, and CAR T/NK still in the early stages. Most therapeutic targets are related to the VEGF pathway, which indirectly confirms the predominant role of TKI-ICI combination therapy in HCC treatment. Most targets have low safety and poor specificity. However, RRM2, KDR, and AURKA have strong safety and specificity, showing excellent prospects for targeted HCC therapy.

This study analyzed and summarized the overview of HCC clinical trials and the safety and specificity of therapeutic targets, providing a reference for HCC clinical research.

Recent advances in the systemic treatment of advanced hepatocellular carcinoma (HCC) with immunotherapy have once again reignited discussion over the role of combined therapy in earlier stages. This year, different international meetings have presented recent results from clinical trials on adjuvant therapy alone (IMBrave-050) and combined with transarterial chemoembolization (EMERALD-1 and LEAP-12). Increased enthusiasm for the use of adjuvant and neoadjuvant therapy for liver transplantation, surgery, and local-regional treatment of HCC has been shown. However, the initial results from these trials should be interpreted cautiously as we wait for final analyses and effects on overall survival. In this position paper from the special interest group from the Latin American Association for the Study of Liver Diseases (ALEH), we underline the caveats of the applicability of these potential treatments in our region, explore points of agreement, and highlight areas of uncertainty. Moreover, we underscore the role of hepatologists in the clinical decision-making process and management of these patients.

Hepatocellular carcinoma (HCC) with microvascular invasion (MVI) is associated with high recurrence and poor survival outcomes. Although adjuvant therapies such as transcatheter arterial chemoembolization (TACE), targeted therapy, and immunotherapy show potential in improving outcomes, the optimal postoperative treatment strategy remains undetermined. This study evaluates the efficacy of different adjuvant treatments on disease-free survival (DFS) and overall survival (OS) in HCC patients with MVI following curative resection.

A retrospective cohort of 409 HCC patients with MVI who underwent curative resection from three clinical centers between 2017 and 2024 was analyzed. Patients were stratified into three groups: TACE alone (n=132), TACE + targeted therapy (n=58), and TACE + targeted immunotherapy (n=68). Propensity score matching (PSM) was employed to balance confounding factors. Kaplan-Meier survival curves and Cox regression models were used to assess DFS and OS. A nomogram was constructed for individualized DFS prediction.

After PSM, both the TACE + targeted therapy and TACE + targeted immunotherapy groups exhibited significantly prolonged DFS compared to TACE alone (median DFS: 16 vs 22 and 21 months, respectively; p=0.027). No significant differences were observed in OS across the groups. The nomogram for DFS demonstrated robust predictive performance, with a C-index of 0.709 and 0.645 in the training and validation cohorts, respectively, supporting its utility in clinical decision-making.

In HCC patients with MVI, adjuvant TACE combined with targeted therapy or targeted immunotherapy significantly enhances DFS, though no OS benefit was observed. The developed nomogram provides a reliable tool for risk stratification and personalized postoperative management in this high-risk patient population.

Hepatocellular carcinoma remains a life-threatening malignancy with limited therapeutic options following the failure of second-line treatments1,2. Oncolytic viruses selectively replicate in and lyse cancer cells, releasing neoantigens and stimulating systemic antitumour immunity3, offering a potential therapeutic option. Here we present the results of a multicentre phase 1 clinical trial evaluating VG161, an engineered oncolytic herpes simplex virus that expresses IL-12, IL-15, IL-15Rα and a PD-1-PD-L1-blocking fusion protein4, for safety and efficacy in patients with advanced liver cancer. VG161 was well tolerated, with no dose-limiting toxicities observed, and it demonstrated promising efficacy by reshaping the tumour immune microenvironment and re-sensitizing tumours that were previously resistant to systemic treatments. Notably, we also found that patients who had previously been sensitive to checkpoint inhibitor therapy showed enhanced efficacy with VG161 treatment. Furthermore, we developed an efficacy-prediction model based on differentially expressed genes, which successfully identified patients who were likely to benefit from VG161 and predicted prolonged overall survival. These findings position VG161 as a promising third-line therapeutic option for refractory hepatocellular carcinoma. This provides a new avenue for treatment and advances the field of oncolytic virus-based immunotherapies. ClinicalTrials.gov registration: NCT04806464 .

Signal transducer and activator of transcription 3 is a transcription factor that is essential for the survival and immune sequestration of cancer cells. We conducted a phase I study of TTI-101, a first-in-class, selective small-molecule inhibitor of signal transducer and activator of transcription 3, in patients with advanced metastatic cancer.

Patients were treated with TTI-101 orally twice daily in 28-day cycles at four dose levels (DL): 3.2 (DL1), 6.4 (DL2), 12.8 (DL3), and 25.6 (DL4) mg/kg/day ("3+3" design). Three TTI-101 formulations were used in a stepwise manner (NCT03195699).

Sixty-four patients were treated (median age, 63 years; male sex, 52%; median number of prior therapies, 3). No dose-limiting toxicities or fatal treatment-related adverse events (TRAE) were observed. Diarrhea (mostly grade 1/2) was the only TRAE observed in ≥30% of subjects. Five patients experienced grade 3 TRAEs that resolved. TTI-101 showed linear pharmacokinetics from DL1 to DL3, with the pharmacokinetics plateauing at DL3. The recommended phase II dose is 12.8 mg/kg/day (DL3). Of the 41 patients who were evaluable for response, five (12%) had confirmed partial responses (cPR) and 17 (41%) had stable disease. Three (18%) of the 17 patients with hepatocellular carcinoma had a cPR (median time to treatment failure, 10.6 months). Two other cPRs were noted in one patient with ovarian cancer and one patient with gastric cancer.

TTI-101 was well tolerated. cPRs were observed across tumor types. The antitumor activity of TTI-101 monotherapy in patients with advanced, metastatic solid tumors is promising. A phase II study of TTI-101 in hepatocellular carcinoma is currently underway.

The incidence and mortality of hepatocellular carcinoma are still high according to National Cancer Center of China. Atezolizumab plus bevacizumab has become one of the standard regimens for the first-line treatment of unresectable hepatocellular carcinoma. However, some patients still use lenvatinib in combination with immunotherapy instead of a standard "atezolizumab-bevacizumab" regimen as a lower risk of bleeding in patients with esophagogastric varices. However, there is no evidence for second-line therapy after progression on lenvatinib combined with PD-1 inhibitor in unresectable hepatocellular carcinoma till now. Herein, we aim to investigate second-line treatment among these patients.

Thirty-three patients with unresectable hepatocellular carcinoma with esophagogastric varices were admitted to the Second Affiliated Hospital of Nanchang University from January 2019 to December 2023. They were treated with lenvatinib in combination with PD-1 inhibitor as first line. The efficacy was conducted according to the RECIST1.1 criteria. The endpoints included objective response rate (ORR), disease control rate (DCR), median overall survival (OS), and median progression free survival (PFS).

We identified a total of 225 patients with unresectable hepatocellular carcinoma with esophagogastric varices who received first-line lenvatinib in combination with PD-1 inhibitor, of whom 33 (14.7%) received second-line therapy. 21 patients (63.6%) were treated with regorafenib combined with PD-1 inhibitor, 6 patients (18.2%) with apatinib plus PD-1 inhibitor, 4 patients (12.1%) with bevacizumab plus PD-1 inhibitor, and the remaining 2 patients with regorafenib or sorafenib as monotherapy, respectively. Of the 33 patients, 2 (6.1%) were evaluated as partial response (PR), 16 (48.5%) had stable disease (SD), and 15 (45.4%) experienced progression (PD). The ORR was 6.1%, and the DCR was 54.6%. Median PFS was 4.5 months, median OS was 7.2 months, and the 12-month OS rate was 27.3%. Overall survival follow-up was done in 37 patients without second line treatment whose baseline levels were matched with those of the treatment group. The OS was 7.2 months in second line treatment group versus 3.0 months in control group (p = 0.04). As for different treatments in a second line, The ORR of regorafenib in combination with PD-1 inhibitor was 9.5%, the DCR was 47.6%, the median PFS was 4.2 months, and the median OS was 5.9 months. None of the patients treated with apatinib plus PD-1 inhibitor got PR, the DCR was 83.3%, the median PFS was 8.7 months, and the median OS was 9.1 months. None of the patients treated with bevacizumab plus PD-1 inhibitor got PR, the DCR was 25.0%, the median PFS was 2.2 months, and the median OS was 6.0 months.

The second-line treatment of unresectable hepatocellular carcinoma with esophagogastric varices after progression on first-line lenvatinib combined with PD-1 inhibitor is effective. Regorafenib or apatinib combined with PD-1 inhibitor might be the preferred options.

Systemic treatment for unresectable hepatocellular carcinoma (HCC) has rapidly advanced, with immune checkpoint inhibitors now the preferred first-line option. However, with multiple agents available and no established treatment sequence, selecting the most suitable second-line (2L) therapy remains challenging. While sorafenib is frequently chosen for 2L treatment, comprehensive data supporting its use is limited. This study evaluates the effectiveness of sorafenib as 2L therapy and factors influencing outcomes following first-line treatment failure in advanced HCC patients.

This is a retrospective, multicenter study, including 81 patients with unresectable HCC from 12 European centers who received sorafenib as 2L treatment. Median overall survival (mOS), median progression-free survival (mPFS), radiological response to treatment, and toxicity were evaluated. Univariable and multivariable analyses were performed to identify potential predictors of clinical benefit.

In this cohort, some patients were treated with 2L sorafenib mOS for 7.4 months (95% CI: 6.6-13.6) and other patients were treated with mPFS for 3.7 months (95% CI: 3.0-4.8). Multivariable analysis revealed the best median OS for patients with CP A and AFP levels < 400 ng/mL (15.5 months). Adverse events (AE) of grade ≥ 3 were reported in 59.4% of patients.

In this real-world cohort of European patients with unresectable HCC, the outcome of sorafenib treatment in the 2L setting was comparable to that of the other established 2L treatment options in patients with preserved liver function and good performance status. This study contributes to the understanding of the role of sorafenib in the 2L setting and underscores the need for further research to identify predictive factors for response and survival in order to optimize treatment algorithms for advanced HCC.

Hepatic arterial infusion chemotherapy (HAIC) has emerged as a promising treatment for unresectable hepatocellular carcinoma (HCC). However, the safety profiles of HAIC and its various combination therapies remain to be systematically evaluated.

We systematically searched PubMed, Embase, Cochrane Library, and Web of Science databases from inception to November 2024. Studies reporting adverse events (AEs) of HAIC monotherapy or combination therapies in HCC were included. The severity and frequency of AEs were analyzed according to different treatment protocols.

A total of 58 studies (11 prospective, 47 retrospective) were included. HAIC monotherapy demonstrated relatively mild toxicity, primarily affecting hepatobiliary (transaminase elevation 53.2%, hypoalbuminemia 57.2%) and hematological systems (anemia 43.0%, thrombocytopenia 35.2%). HAIC with targeted therapy showed increased adverse events, including characteristic reactions like hand-foot syndrome (48.0%) and hypertension (49.9%). HAIC combined with targeted, and immunotherapy exhibited the highest adverse reaction rates (neutropenia 82.9%, transaminase elevation 97.1%), while HAIC with anti-angiogenic and immunotherapy showed a relatively favorable safety profile. Prospective studies consistently reported higher incidence rates than retrospective studies, suggesting potential underreporting in clinical practice.

Different HAIC-based regimens exhibit distinct safety profiles requiring individualized management approaches. We propose a comprehensive framework for patient selection, monitoring strategies, and AE management. These recommendations aim to optimize treatment outcomes while minimizing adverse impacts on patient quality of life.

Lenvatinib (LEN) is the recommended first-line therapy for unresectable hepatocellular carcinoma (uHCC), but resistance frequently develops, and limited data exist on second-line treatments. This study evaluated the efficacy and safety with a focus on the sorafenib (SOR) or regorafenib (REG)- based monotherapy or combination therapy in patients with uHCC after failure of first-line LEN.

Patients with first-line LEN failure between May 2018 and December 2023 were retrospectively collected. Based on second-line regimens, 70 patients were divided into two groups: the TKI group (n = 21) and the TKI-ICI group (n = 49). Overall survival (OS) and progression-free survival (PFS) were analyzed by Kaplan-Meier methods, and multivariate analysis was performed to identify prognostic factors.

In the TKI-ICI group, median PFS was 5.27 months and median OS was 12.53 months. In the TKI group, median PFS was 3.10 months and median OS was 7.50 months. The objective response rate (ORR) was 19.1% in the TKI group and 16.3% in the TKI-ICI group. The disease control rate (DCR) was 85.7% in the TKI-ICI group and 61.9% in the TKI group. In the TKI-ICI cohort, multivariable Cox analysis revealed the high albumin to neutrophil ratio index (ANRI) was an independent predictor for PFS, while alpha-fetoprotein > 400 ng/mL was the independent predictor for OS. Safety profiles in both cohorts showed manageable toxicity, with no treatment-related deaths.

The combination of TKI and ICI presents a promising second-line treatment option after LEN failure, regardless of the specific second-line TKI used.

Macrovascular invasion (MVI) is a strong prognostic factor for advanced hepatocellular carcinoma (HCC). The current criteria for radiological assessment are unclear in evaluating the impact of MVI on systemic therapy. In this study, we standardized the assessment of MVI and validated its clinical relevance.

Clinical data were collected from patients with advanced HCC and MVI who received first-line systemic therapy at four medical centers in Japan. First, we used MVI progressive disease (MVI-PD) to track MVI progression and Response Evaluation Criteria in Solid Tumors version 1.1 progressive disease (RECIST v1.1-PD) to evaluate tumor enlargement other than MVI and the appearance of new lesions. Next, we assessed the prognostic value of MVI-PD and RECIST v1.1-PD.

Of the 207 advanced HCC patients with MVI, 189 received appropriate imaging evaluation. Forty (21.2%) patients had MVI-PD and RECIST v1.1-PD, 51 (27.0%) had prior MVI-PD, and 61 (32.3%) had prior RECIST v1.1-PD. In a landmark analysis, the prognosis of 163 patients who survived more than 3 months was analyzed based on the assessment of imaging response during the first 3 months. The median overall survival (OS) was 5.4 months in those who had MVI-PD and RECIST v1.1-PD, 7.4 months in those who had RECIST v1.1-PD only, 7.2 months in those who had MVI-PD only, and 19.7 months in patients who had neither (p < 0.001). The correlation coefficients between progression-free survival and OS in patients with appropriate imaging assessments were similar for MVI-PD (0.515) and RECIST v1.1-PD (0.498).

Our findings demonstrate the link between MVI progression and poor OS in systemic therapy for advanced HCC, emphasizing the importance of an accurate method for assessing MVI progression.

The combination of regorafenib and immune checkpoint inhibitor (ICI) has been the most popular second-line systemic therapy for advanced hepatocellular carcinoma (HCC). However, considering the good anti-tumor performance of lenvatinib, combined immunotherapy on the basis of lenvatinib after first-line lenvatinib failure is also popular in clinical practice. This study aimed to compare the efficacy and safety of regorafenib plus ICI (TACE-R-I) versus lenvatinib plus ICI (TACE-L-I) in patients with advanced HCC after lenvatinib failure.

In this single-center retrospective study, 164 patients with advanced HCC were enrolled from January 2019 to March 2024 in China. All patients were aged ≥ 18 years, clinically or pathologically diagnosed with HCC. All patients received trans-arterial chemoembolization (TACE) as local treatment. Overall survival (OS), progression-free survival (PFS), and treatment-related adverse events (TRAEs) were compared between groups. The Cox regression model was used to analyze the factors associated with OS and PFS.

We compared 77 patients from each group after propensity score matching (PSM). There was no significant difference in the OS (p = 0.255) or PFS (p = 0.387) between groups. However, in the subgroup (distant metastases, Barcelona Clinic Liver Cancer (BCLC) stage C or tumor thrombus), the TACE-R-I group showed better survival benefit than the TACE-L-I group. The multivariable Cox regression model suggested that BCLC stage and alpha-fetoprotein (AFP) were independently associated with OS. Distant metastases, tumor thrombus and Child-Pugh were independent associated factors for PFS (p < 0.05). The frequency of grade ≥ 3 TRAEs was not significantly different between groups (p ≥ 0.05).

Our study demonstrated that in patients with greater tumor burden, the TACE-R-I group showed better OS and PFS benefits than the TACE-L-I group. However, in the overall population of HCC patients, there was no significant difference in efficacy and safety between the groups.

Liver transplantation (LT) is a curative strategy for hepatocellular carcinoma (HCC), but the risk of HCC recurrence remains a challenging problem. In patients with HCC recurrence after LT (HCC-R_LT), the locoregional and surgical approaches are complex, and the guidelines do not report evidence-based strategies for the management of immunosuppression. In recent years, immunotherapy has become an effective option for patients with advanced HCC in pre-transplant settings. However, due to the risk of potentially fatal allograft rejection, the use of immunotherapy is avoided in post-transplant settings. Combining immunosuppressants with immunotherapy in transplant patients is also challenging due to the complex tumor microenvironment and immunoreactivity. The fear of acute liver rejection and the lack of predictive factors hinder the successful clinical application of immunotherapy for post-liver transplantation HCC recurrence. This review aims to comprehensively summarize the risk of HCC-R_LT, the available evidence for the efficacy of immunotherapy in patients with HCC-R_LT, and the clinical issues regarding the innovative management of this patient population.

Anaplastic lymphoma kinase (ALK) dysregulation is implicated in numerous cancers. Tyrosine kinase inhibitors (TKIs) targeting ALK have improved disease outcomes, but resistance mechanisms are common. This first-in-human trial evaluates ESK-440, a dual inhibitor of ALK and focal adhesion kinase, as a novel strategy for cancers with resistance to ALK-targeting TKIs.

This phase 1, open-label, dose-finding study evaluated the maximum tolerated dose (MTD), safety, efficacy, and pharmacokinetics of ESK-440 in participants with advanced or metastatic solid tumors (ClinicalTrials.gov: NCT01922752). A 3 + 3 dose-escalation design, with daily doses ranging from 25 to 700 mg/day of ESK-440 for each 28-day treatment cycle (6 to 8 cycles) was utilized to identify the MTD. A phase 1b was planned to further evaluate ESK-440 safety and antitumor activity at the MTD but was not performed due to sponsor decision.

32 participants were enrolled and 24 (75 %) completed cycle 1 of treatment. Three dose-limiting toxicities, all grade 3 nausea, were reported (n = 1, 500 mg; n = 2, 700 mg). The MTD was determined to be 500 mg daily. The most frequent adverse events (AEs) were fatigue and nausea (53 % each) and vomiting (38 %). Seven participants (22 %) withdrew from treatment due to AEs and 4 deaths occurred, none related to ESK-440. No participant had a complete or partial response; the best overall response was stable disease in 7 participants.

ESK-440 was safe and tolerable with a maximum tolerated dose of 500mg daily; however, the study was terminated early based on sponsor decision.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors, characterized by high incidence and mortality rates. Due to its insidious onset, most patients are diagnosed at an advanced stage, often missing the opportunity for surgical resection. Consequently, systemic treatments play a pivotal role. In recent years, an increasing number of drugs have been approved for first-line systemic treatment of HCC. However, their efficacy is limited, and some patients develop drug resistance after a period of treatment. For such patients, there is currently a lack of standard second-line systemic treatment options. This review summarizes the latest advancements in second-line systemic treatment research for HCC patients who have developed resistance to various first-line systemic treatments, aiming to provide more rational and personalized second-line treatment strategies.

Portal and hepatic vein tumor thrombosis is associated with inferior outcomes in patients with hepatocellular carcinoma (HCC), and systemic treatment alone is often insufficient. This phase II trial evaluated the efficacy and safety of combining sorafenib with radiotherapy in advanced HCC with thrombosis.

Registered at ClinicalTrials.gov (NCT03535259), this phase II single-arm prospective trial targeted patients with HCC with portal or hepatic vein tumor thrombosis, liver minus gross tumor volume >700 ml, and Eastern Cooperative Oncology Group Performance Status scores of 0 or 1. Participants underwent 40-66 Gy radiotherapy for the hepatic primary tumor and vein tumor thrombosis, with concurrent oral sorafenib (400 mg twice daily) until disease progression or unacceptable adverse events. The primary endpoint was median overall survival (mOS) and the secondary endpoints included overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and Modified Response Evaluation Criteria in Solid Tumors (mRECIST), median progression-free survival (mPFS), time to tumor progression (TTP), tumor thrombosis control, and grade ≥3 adverse events.

Between May 2018 and January 2020, 86 patients were enrolled with a median radiotherapy dose of 54 Gy (40-65 Gy). At a median follow-up of 17.2 months, mOS, mPFS, and TTP stood at 16.5, 6.1, and 6.8 months, respectively. ORR reached 47.7% and 52.3% per RECIST and mRECIST, respectively. For the tumor thrombosis, 2-year control rates per mRECIST were 93.1%. No grade 5 adverse events were noted, whereas thrombocytopenia (22.1%) and leukopenia (14.0%) were the main grade 3 adverse events.

Concurrent sorafenib and radiotherapy is an effective and well-tolerated treatment for patients with HCC with portal or hepatic vein tumor thrombosis.

Treatment options for patients with hepatocellular carcinoma (HCC) and vascular tumor thrombus are limited. The efficacy and safety of concurrent sorafenib and radiation for HCC with portal or hepatic vein tumor thrombosis has not been elucidated. This phase II trial shows that concurrent sorafenib and radiotherapy is effective and well-tolerated in the treatment of advanced HCC with portal vein or hepatic vein tumor thrombosis.

This study is registered at ClinicalTrials.gov (NCT03535259).

Hepatocellular carcinoma (HCC) represents a global health challenge, and ranks among one of the most prevalent and deadliest cancers worldwide. Therapeutic advances have expanded the treatment armamentarium for patients with advanced HCC, but obstacles remain. Precision oncology, which aims to match specific therapies to patients who have tumours with particular features, holds great promise. However, its implementation has been hindered by the existence of numerous 'HCC influencers' that contribute to the high inter-patient heterogeneity. HCC influencers include tumour-related characteristics, such as genetic alterations, immune infiltration, stromal composition and aetiology, and patient-specific factors, such as sex, age, germline variants and the microbiome. This Review delves into the intricate world of HCC, describing the most innovative model systems that can be harnessed to identify precision and/or personalized therapies. We provide examples of how different models have been used to nominate candidate biomarkers, their limitations and strategies to optimize such models. We also highlight the importance of reproducing distinct HCC influencers in a flexible and modular way, with the aim of dissecting their relative contribution to therapy response. Next-generation HCC models will pave the way for faster discovery of precision therapies for patients with advanced HCC.

Neovascularization is an important process in brain tumor development, invasion and metastasis. Several research studies have indicated that the VEGF signaling target has potential for reducing angiogenesis in brain tumors. However, targeting VEGF signaling has not met the expected efficacy, despite initial enthusiasm. This is partly because tumors cleverly use alternative growth factor pathways, other than VEGF signaling, to restore angiogenesis. Multi-target inhibitors have been developed to inhibit several receptor kinases that play a role in the development of angiogenesis. By simultaneously affecting various receptor kinases, these treatments can potentially obstruct various angiogenic pathways that are involved in brain cancer advancement, often offering a more holistic strategy than treatments focusing on just one kinase. Since 2009, the FDA has approved a number of multi-kinase inhibitors that target angiogenic growth factor receptors (e.g., VEGFR, PDGFR, FGFR, RET, c-KIT, MET, AXL and others) for treatment of malignant diseases, including brain cancer. Here, we present some recent results from the literature regarding the preclinical and clinical effects of these inhibitors on brain tumors.

The incidence and mortality rates of liver cancer in China remain elevated. Although early-stage liver cancer is amenable to surgical resection, a significant proportion of patients are diagnosed at advanced stages. Currently, in addition to surgical resection for hepatocellular carcinoma, the primary treatment modalities predominantly include chemotherapy. The widespread use of chemotherapy, which non-selectively targets both malignant and healthy cells, often results in substantial immunosuppression. Simultaneously, the accumulation of chemotherapeutic agents can readily induce drug resistance upon reaching the physiological threshold, thereby diminishing the efficacy of these treatments. Besides chemotherapy, there exist targeted therapy, immunotherapy and other therapeutic approaches. Nevertheless, the development of drug resistance remains an inevitable challenge. To address these challenges, we turn to nanomedicine, an emerging and widely utilized discipline that significantly influences medical imaging, antimicrobial strategies, drug delivery systems, and other related areas. Stable and safe nanomaterials serve as effective carriers for delivering anticancer drugs. They enhance the precision of drug targeting, improve bioavailability, and minimize damage to healthy cells. This review focuses on common nanomaterial carriers used in hepatocellular carcinoma (HCC) treatment over the past five years. The following is a summary of the three drugs: Sorafenib, Gefitinib, and lenvatinib. Each drug employs distinct nanomaterial delivery systems, which result in varying levels of bioavailability, drug release rates, and therapeutic efficacy.

Glioblastoma multiforme (GBM) is the most prevalent and aggressive primary brain tumor in adults, characterized by a poor prognosis and significant resistance to existing treatments. Despite progress in therapeutic strategies, the median overall survival remains approximately 15 months. A hallmark of GBM is its intricate molecular profile, driven by disruptions in multiple signaling pathways, including PI3K/AKT/mTOR, Wnt, NF-κB, and TGF-β, critical to tumor growth, invasion, and treatment resistance. This review examines the epidemiology, molecular mechanisms, and therapeutic prospects of targeting these pathways in GBM, highlighting recent insights into pathway interactions and discovering new therapeutic targets to improve patient outcomes.

Over the past several years, the therapeutic landscape for patients with advanced, unresectable, or metastatic hepatocellular carcinoma has been transformed by the incorporation of checkpoint inhibitor immunotherapy into the treatment paradigm. Frontline systemic treatment options have expanded beyond anti-angiogenic tyrosine kinase inhibitors, such as sorafenib, to a combination of immunotherapy approaches, including atezolizumab plus bevacizumab and durvalumab plus tremelimumab, both of which have demonstrated superior response and survival to sorafenib. Additionally, combination treatments with checkpoint inhibitors and tyrosine kinase inhibitors have been investigated with variable success. In this review, we discuss these advances in systemic treatment with immunotherapy, with a focus on understanding both the underlying biology and mechanism of these strategies and their efficacy outcomes in clinical trials. We also review challenges in identifying predictive biomarkers of treatments and discuss future directions with novel immunotherapy targets.

In addition to their traditional roles in maintaining tissue morphology and organ development, emerging evidence suggests that collagen (COL) remodeling-referring to dynamic changes in the quantity, stiffness, arrangements, cleavage states, and homo-/hetero-trimerization of COLs-serves as a key signaling mechanism that governs tumor growth and metastasis. COL receptors act as switches, linking various forms of COL remodeling to different cell types during cancer progression, including cancer cells, immune cells, and cancer-associated fibroblasts. In this review, we summarize recent findings on the signaling pathways mediated by COL arrangement, cleavage, and trimerization states (both homo- and hetero-), as well as the roles of the primary COL receptors-integrin, DDR1/2, LAIR-1/2, MRC2, and GPVI-in cancer progression. We also discuss the latest therapeutic strategies targeting COL fragments, cancer-associated fibroblasts, and COL receptors, including integrins, DDR1/2, and LAIR1/2. Understanding the pathways modulated by COL remodeling and COL receptors in various pathological contexts will pave the way for developing new precision therapies.

In this manuscript, we comment on the article by Zhou et al, who assessed the efficacy of hepatic arterial infusion chemotherapy (HAIC) and its combination strategies for advanced hepatocellular carcinoma (HCC) using network meta-analysis methodology. We focus specifically on the potential advantages and role of HAIC in the treatment algorithm for advanced HCC. However, there remains numerous knowledge gaps before the role of HAIC can be established. There is significant heterogeneity of HAIC regimes with difficult interpretation of the clinical outcomes. Additionally, there is a lack of direct comparative data between HAIC, systemic chemotherapy, novel immunotherapies and targeted therapies. The underlying biochemical mechanisms that might explain the efficacy of HAIC and its effect on the HCC microenvironment requires further research. In the developing era of nanotechnology and targeted drug delivery systems, there is potential for integration of HAIC with novel technologies to effectively treat advanced HCC whilst minimising systemic complications.

Hepatocellular carcinoma (HCC) is a major cause of cancer-related deaths globally, and the need for effective systemic therapies for HCC is urgent. Our previous work reveals that Pin1 is a potential anti-HCC target, which regulates miRNA biogenesis and identifies API-1 as a novel Pin1 inhibitor to suppresses HCC. However, a great demand in HCC therapy as well as the limited chemical stability and pharmacokinetic feature of API-1 motivated us to find improved Pin1 inhibitors. Herein, we designed and synthesized diverse 6-O-benzylguanine derivatives and discovered API-32 as a novel Pin1 inhibitor with better stability and pharmacokinetic property over API-1. API-32 directly interacted with the Pin1 PPIase domain to inhibit Pin1 activity. API-32 significantly suppressed the cell proliferation and migration of HCC cells by blocking Pin1's downstream signal. Moreover, API-32 exhibited an enhanced inhibitory function against the HCC tumor in mice models without obvious toxicity, making it a promising drug candidate for HCC treatment.

Liver cancer represents a major global health concern, with projections indicating that the number of new cases could surpass 1 million annually by 2025. Hepatocellular carcinoma (HCC) constitutes around 90% of liver cancer cases and is primarily linked to factors incluidng aflatoxin, hepatitis B (HBV) and C (HCV), and metabolic disorders. There are no obvious symptoms in the early stage of HCC, which often leads to delays in diagnosis. Therefore, HCC patients usually present with tumors in advanced and incurable stages. Several signaling pathways are dis-regulated in HCC and cause uncontrolled cell propagation, metastasis, and recurrence of HCC. Beyond the frequently altered and therapeutically targeted receptor tyrosine kinase (RTK) pathways in HCC, pathways involved in cell differentiation, telomere regulation, epigenetic modification and stress response also provide therapeutic potential. Investigating the key signaling pathways and their inhibitors is pivotal for achieving therapeutic advancements in the management of HCC. At present, the primary therapeutic approaches for advanced HCC are tyrosine kinase inhibitors (TKI), immune checkpoint inhibitors (ICI), and combination regimens. New trials are investigating combination therapies involving ICIs and TKIs or anti-VEGF (endothelial growth factor) therapies, as well as combinations of two immunotherapy regimens. The outcomes of these trials are expected to revolutionize HCC management across all stages. Here, we provide here a comprehensive review of cellular signaling pathways, their therapeutic potential, evidence derived from late-stage clinical trials in HCC and discuss the concepts underlying earlier clinical trials, biomarker identification, and the development of more effective therapeutics for HCC.