Antibody-platinum(IV)prodrugs conjugates for targeted treatment of cutaneous squamous cell carcinoma

Antibody-drug conjugates(ADCs)are a new type of targeting antibodies that conjugate with highly toxic anticancer drugs via chemical linkers to exert high specificity and efficient killing of tumor cells,thereby attracting considerable attention in precise oncology therapy.Cetuximab(Cet)is a typical antibody that offers the benefits of good targeting and safety for individuals with advanced and inoperable cutaneous squamous cell carcinoma(cSCC);however,its anti-tumor activity is limited to a single use.Cisplatin(CisPt)shows good curative effects;however,its adverse effects and non-tumor-targeting ability are major drawbacks.In this study,we designed and developed a new ADC based on a new cytotoxic platinum(IV)prodrug(C8Pt(IV))and Cet.The so-called antibody-platinum(IV)prodrugs conjugates,named Cet-C8Pt(IV),showed excellent tumor targeting in cSCC.Specifically,it accurately delivered C8Pt(IV)into tumor cells to exert the combined anti-tumor effect of Cet and CisPt.Herein,metabolomic analysis showed that Cet-C8Pt(IV)promoted cellular apoptosis and increased DNA damage in cSCC cells by affecting the vitamin B6 metabolic pathway in tumor cells,thereby further enhancing the tumor-killing ability and providing a new strategy for clinical cancer treatment using antibody-platinum(IV)prodrugs conjugates.

Lipid metabolism of hepatocellular carcinoma impacts targeted therapy and immunotherapy

Hepatocellular carcinoma(HCC)is a common malignant tumor that affecting many people's lives globally.The common risk factors for HCC include being overweight and obese.The liver is the center of lipid metabolism,synthesizing most cholesterol and fatty acids.Abnormal lipid metabolism is a significant feature of metabolic reprogramming in HCC and affects the prognosis of HCC patients by regulating inflammatory responses and changing the immune microenvironment.Targeted therapy and immunotherapy are being explored as the primary treatment strategies for HCC patients with unresectable tumors.Here,we detail the specific changes of lipid metabolism in HCC and its impact on both these therapies for HCC.HCC treatment strategies aimed at targeting lipid metabolism and how to integrate them with targeted therapy or immunotherapy rationally are also presented.

Role of autophagy in tumorigenesis,metastasis,targeted therapy and drug resistance of hepatocellular carcinoma

Autophagy is a "self-degradative" process and is involved in the maintenance of cellular homeostasis and the control of cellular components by facilitating the clearance or turnover of long-lived or misfolded proteins, protein aggregates, and damaged organelles. Autophagy plays a dual role in cancer, including in tumor progression and tumor promotion, suggesting that autophagy acts as a double-edged sword in cancer cells. Liver cancer is one of the greatest leading causes of cancer death worldwide due to its high recurrence rate and poor prognosis. Especially in China, liver cancer has become one of the most common cancers due to the high infection rate of hepatitis virus. In primary liver cancer, hepatocellular carcinoma (HCC) is the most common type. Considering the perniciousness and complexity of HCC, it is essential to elucidate the function of autophagy in HCC. In this review, we summarize the physiological function of autophagy in cancer, analyze the role of autophagy in tumorigenesis and metastasis, discuss the therapeutic strategies targeting autophagy and the mechanisms of drug-resistance in HCC, and provide potential methods to circumvent resistance and combined anticancer strategies for HCC patients.

Hepatic cancer stem cells and drug resistance: Relevance in targeted therapies for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of most common malignancies in the world. Systemic treatments for HCC, particularly for advanced stages, are limited by the drug resistance phenomenon which ultimately leads to therapy failure. Recent studies have indicated an association between drug resistance and the existence of the cancer stem cells (CSCs) as tumor initiating cells. The CSCs are resistant to conventional chemotherapies and might be related to the mechanisms of the ATP Binding Cassette (ABC) transporters and alterations in the CSCs signaling pathways. Therefore, to contribute to the development of new HCC treatments, further information on the characterization of CSCs, the modulation of the ABC transporters expression and function and the signaling pathway involved in the self renewal, initiation and maintenance of the cancer are required. The combination of transporters modulators/inhibitors with molecular targeted therapies may be a potent strategy to block the tumoral progression. This review summarizes the association of CSCs, drug resistance, ABC transporters activities and changes in signaling pathways as a guide for future molecular therapy for HCC.

Roles of conventional and complementary therapies in recurrent hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is the fifth most common type of cancer and the fourth leading cause of cancer-related deaths in the world.HCC has a reported recurrence rate of 70%-80%after 5 years of follow-up.Controlling tumor recurrence is the most critical factor associated with HCC mortality.Conventional salvage therapies for recurrent HCC include re-hepatectomy or liver transplantation,transcatheter arterial chemoembolization,Y-90,target therapy,and immunotherapy;however,these conventional treatment modalities have yet to achieve consistently favorable outcomes.Meanwhile,previous studies have demonstrated that conventional therapies in combination with traditional Chinese medicine(TCM),acupuncture,moxibustion or dietary supplements could notably benefit patients with HCC recurrence by strengthening and augmenting the overall management strategy.However,systemic reviews related to the interactions between complementary therapies and conventional therapy in recurrent HCC are limited.In this review,we discuss the molecular mechanisms underlying the functions of complementary therapies for recurrent HCC,which include augmenting the local control to improve the congestion status of primary tumors and reducing multicentric tumor occurrence via inducing autophagy,apoptosis or cell cycle arrest.TCM and its derivatives may play important roles in helping to control HCC recurrence by inhibiting epithelial-mesenchymal transition,migration,invasion,and metastasis,inhibiting cancer stem cells,and ameliorating drug resistance.

Hepatocellular carcinoma and multidrug resistance: Past, present and new challenges for therapy improvement

Hepatocellular carcinoma(HCC) is the most frequent form of liver cancer and the third most common cause of cancer-related death in the world. The main risk factor worldwide for this type of malignancy is chronic hepatitis caused by hepatitis B virus and hepatitis C virus infections. Advances in early detection and treatmenthave improved life expectancy of patients with HCC. However, this disorder remains as a disease with poor prognosis. In fact, epidemiological studies have revealed that there is an 8-mo median survival rate in patients, approximately 20% of whom survive one year while only 5% remain alive after three years. Additionally, HCC is particularly difficult to treat because of its high recurrence rate, and its resistance to conventional chemotherapy is due, among other mechanisms, to several members of the ATP-Binding Cassette protein family involved in drug transport being overexpressed. Fortunately, there is evidence that these patients may benefit from alternative molecular-targeted therapies. This manuscript intends to provide further insight into the etiology and molecular mechanisms related to HCC development and the latest therapeutic approaches to treat this malignancy. The development of effective delivery systems of antitumor drugs able to target the liver parenchyma is also assessed. Finally, the prospects in the development of more efficient drug therapies to overcome multidrug resistance are also examined.

Role of deubiquitinase JOSD2 in the pathogenesis of esophageal squamous cell carcinoma

BACKGROUND Esophageal squamous cell carcinoma(ESCC)is a deadly malignancy with limited treatment options.Deubiquitinases(DUBs)have been confirmed to play a crucial role in the development of malignant tumors.JOSD2 is a DUB involved in con-trolling protein deubiquitination and influencing critical cellular processes in cancer.AIM To investigate the impact of JOSD2 on the progression of ESCC.METHODS Bioinformatic analyses were employed to explore the expression,prognosis,and enriched pathways associated with JOSD2 in ESCC.Lentiviral transduction was utilized to manipulate JOSD2 expression in ESCC cell lines(KYSE30 and RESULTS )Preliminary research indicated that JOSD2 was highly expressed in ESCC tissues,which was associated with poor prognosis.Further analysis demonstrated that JOSD2 was upregulated in ESCC cell lines compared to normal esophageal cells.JOSD2 knockdown inhibited ESCC cell activity,including proliferation and colony-forming ability.Moreover,JOSD2 knockdown decreased the drug resistance and migration of ESCC cells,while JOSD2 overexpression enhanced these phenotypes.In vivo xenograft assays further confirmed that JOSD2 promoted tumor proliferation and drug resistance in ESCC.Mechanistically,JOSD2 appears to activate the MAPK/ERK and PI3K/AKT signaling pathways.Mass spectrometry was used to identify crucial substrate proteins that interact with JOSD2,which identified the four primary proteins that bind to JOSD2,namely USP47,IGKV2D-29,HSP90AB1,and PRMT5.CONCLUSION JOSD2 plays a crucial role in enhancing the proliferation,migration,and drug resistance of ESCC,suggesting that JOSD2 is a potential therapeutic target in ESCC.

Research Progress in Targeted Therapy of Hepatocellular Carcinoma

Hepatocellular carcinoma(HCC)is one of the most common malignancies,and its treatment is limited.With the understanding of key genes and signaling pathways in the occurrence and development of HCC,targeted drugs with high selectivity and low toxicity have been developed continuously,bringing a variety of options for the treatment of advanced HCC.In this article,the research progress on representative drugs of targeted therapy and potential therapeutic targets for HCC are reviewed.

Current and novel approaches in the pharmacological treatment of hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is one of the most lethal malignant tumours worldwide.The mortality-to-incidence ratio is up to 91.6%in many countries,representing the third leading cause of cancer-related deaths.Systemic drugs,including the multikinase inhibitors sorafenib and lenvatinib,are first-line drugs used in HCC treatment.Unfortunately,these therapies are ineffective in most cases due to late diagnosis and the development of tumour resistance.Thus,novel pharmacological alternatives are urgently needed.For instance,immune checkpoint inhibitors have provided new approaches targeting cells of the immune system.Furthermore,monoclonal antibodies against programmed cell death-1 have shown benefits in HCC patients.In addition,drug combinations,including first-line treatment and immunotherapy,as well as drug repurposing,are promising novel therapeutic alternatives.Here,we review the current and novel pharmacological approaches to fight HCC.Preclinical studies,as well as approved and ongoing clinical trials for liver cancer treatment,are discussed.The pharmacological opportunities analysed here should lead to significant improvement in HCC therapy.

Neoadjuvant Therapy for Locally Advanced Renal Cell Carcinoma with Sorafenib in a Reference Center in Mexico

Background: neo - adjuvant therapy is usually indicated in locally advanced tumors, the aim is to decrease the tumoral burden and enhance overall survival. Renal cell carcinoma is a chemo and radio resistant neoplasm and this type of approach is not as effective as in other solid tumors. On the other hand immunotherapy is indicated in metastatic disease, demonstrating a better overall survival. Sorafenib is an antiangiogenic drug approved for locally advanced or metastatic RCC. We postulated that it can be used in a neoadjuvant way to decrease the vascularization of selected tumors. Report of the case: 57 years old male referred to our service with a right renal mass and metastatic disease to lumbar spine and suprarenal gland. He was treated with three months of sorafenib previous to the surgery. Results: The patient went into surgery three months after initiating the antiangiogenic drug, during the surgery we found less neo-formance vessels;the dissection was subjectively easier, due to peri-renal edema. The pathologic analysis of the specimen was renal cell carcinoma. Interestingly, 40% of central ischemic (coagulative) necrosis was found. Conclusion: There are no neoadjuvant drugs accepted for the treatment of renal cell carcinoma;using an antiagiogenic drug to decrease the vascular burden characteristic of this type of tumors could be a viable option in selected cases. We used a lower dose of the drug with an acceptable safety profile.

Evaluation of Targeted Therapy for Locally Advanced or Metastatic Renal Cell Carcinoma in Tunisia

Introduction: Renal cell carcinoma (RCC) is known to be chemo resistant but with the introduction of targeted therapies;there has been a “revolution” in its treatment strategies. The only targeted therapy available in Tunisia for the treatment of metastatic and/or locally advanced RCC is sunitinib. Objective of the Study: To evaluate therapeutic results and tolerance of sunitinib in metastatic and/or locally advanced RCC. Subjects and Methods: This was a retrospective study covering a period of six years (from January 2008 to January 2014) conducted in 5 medical oncology departments in Tunisia. The population of the study consisted of 29 patients treated with sunitinib for metastatic and/or locally advanced RCC. Results: The mean age of patients was 51 years. Three patients had tumor recurrence and 26 patients had a metastatic RCC. The prognosis was good for 5 patients, intermediate for 19 patients and poor for 5 patients. The median duration of treatment was 5 months. Because of side effects, treatment was discontinued in 12.5% of cases and the dose was reduced in 10.3% of cases. Side effects consisted of asthenia (95.8%), stomatitis (70.8%), anemia (50%), hand-foot syndrome (55.8%) in addition to nausea and vomiting (54.2%). Objective response was observed in 37.5% of patients after 3 months of treatment and in 50% after 6 months. The median progression-free survival was 14 months (95% CI, 7.9 to 20.6). The median overall survival was 22 months (95% CI, 15.6 to 28.7). Conclusion: The prognosis of RCC in Tunisian patients has clearly improved with the introduction of sunitinib, but other therapies with a proven efficacy as a first and second line therapy should be considered.

Skin toxicity predicts efficacy to sorafenib in patients with advanced hepatocellular carcinoma

AIM:To study the relationship between adverse events(AEs),efficacy,and nursing intervention for sorafenibtherapy in patients with hepatocellular carcinoma(HCC).METHODS:We enrolled 37 consecutive patients withadvanced HCC who received sorafenib therapy.Relationships among baseline characteristics as well as AEoccurrence and tumor response,overall survival(OS),and treatment duration were analyzed.The nursingintervention program consisted of education regardingself-monitoring and AEs management,and telephoneRESULTS:A total of 37 patients were enrolled in the study,comprising 30 males(81%) with a median age of 71 years.The disease control rate at 3 mo was 41%,and the median OS and treatment duration were 259 and 108 d,respectively.Nursing intervention was given to 24 patients(65%).Every patient exhibited some kinds of AEs,but no patients experienced G4 AEs.Frequently observed AEs > G2 included anorexia(57%),skin toxicity(57%),and fatigue(54%).Factors significantly associated with longer OS in multivariate analysis demonstrated that age ≤ 70 years,presence of > G2 skin toxicity,and absence of > G2 hypoalbuminemia.The disease control rate in patients with > G2 skin toxicity was 13/20(65%),which was significantly higher compared with that in patients with no or G1 skin toxicity.Multivariate analysis revealed that nursing intervention and > G2 skin toxicity were independent significant predictors for longer treatment duration.CONCLUSION:Skin toxicity was associated with favorable outcomes with sorafenib therapy for advanced HCC.Nursing intervention contributed to better adher-ence,which may improve the efficacy of sorafenib.

Hepatocellular Carcinoma-Cause,Treatment and Metastasis

In the recent decades, the incidence of hepatocellular carcinoma (HCC) has been found to be increasing in males in some countries. In China, HCC ranked second of cancer mortality since 1990s. Hepatitis B and C viruses (HBV and HCV) and dietary aflatoxin intake remain the major causative factors of HCC. Surgery plays a major role in the treatment of HCC, particularly for small HCC. Downstaging unresectable huge HCC to smaller HCC and followed by resection will probably be a new approach for further study. Liver transplantation is indicated for small HCC, however, some issues remain to be solved.Different modes of 'regional cancer therapy for HCC' have been tried. Systemic chemotherapy has been disappointing in the past but the future can be promising.Biotherapy, such as cytokines, differentiation inducers,anti-angiogenic agents, gene therapy and tumor vaccine will probably play a role, particularly in the prevention of tumor recurrence. HCC invasiveness is currently the major target of study. Tremendous works have been done at the molecular level, which will provide clues for biomarker of HCC progressionas well as targets for intervention.

Clinical characteristics and outcome of a cohort of 101 patients with hepatocellular carcinoma

AIM: To conduct a cohort study of 101 patients with hepatocellular carcinoma (HCC) presenting to a tertiary care medical referral center in Germany between 1997 and 1999. METHODS AND RESULTS: Data were retrospectively analyzed by chart review. In 95 cases (72 males and 23 females) sufficient data were available for analysis. Twenty five (29%) of 85 patients were HBsAg or anti HBc positive, 21/85 (25%) were anti HCV positive, and 6/85 (7%) were positive for both HBV and HCV-markers. Age was significantly lower in HBV positive patients than in the other two groups. Thirty one (34%) of 90 patients had histories of alcohol abuse. In 79/94 (84%) patients, cirrhosis was diagnosed. Of these cirrhotic patients, 29/79 (37%) belonged to Child Pugh's group (CHILD) A, 32/79 (40%) to CHILD B, and 18/79 (23%) to CHILD C. AFP was elevated in 61/91 (67%) patients. A single tumor nodule was found in 38/94 (40%), more than one nodule in 31/94 (34%), and 25/94 (26%) had a diffusely infiltrating tumor, i.e. the tumor margins could not be seen on imaging procedures. Portal vein thrombosis was present in 19/94 (20%). Imaging data consistent with lymph node metastases were found in 10/92 (11%), while distant metastases were found in 8/93 (9%). According to Okuda 28/94 (30%) were grouped to stage I, 53/94 (56%) were grouped to stage II, and 13/94 (14%) were grouped to stage II. Survival data were available for 83 patients. The Kaplan-Meier estimate for median survival was 8 4 months. Factors influencing survival were the Okuda score, the presence of portal vein thrombosis, and the presence of ascites. The presence of non complicated liver cirrhosis by itself, distant metastases, or infection with hepatitis viruses did not influence survival. AFP positivity by itself did not influence survival, though patients with an AFP value greater than 100 microg/L did experience shortened survival. Treatment besides tamoxifen or supportive care was associated with prolonged survival. The influence of therapy on survival was most pronounced in Okuda stage II patients. There was longer survival in those Okuda stage II patients who were treated with percutaneous ethanol injection. CONCLUSION: Even in a low incidence area such as Germany, the majority of HCC is caused by viral hepatitis and therefore potentially preventable. Reflecting the high proportion of advanced stage tumors in our patients, the median survival was poor. Patients who received active therapy had a longer survival.

Pathologic complete response to conversion therapy in hepatocellular carcinoma using patient-derived organoids:A case report

BACKGROUND For primary liver cancer,the key to conversion therapy depends on the effectiveness of drug treatment.Patient-derived tumor organoids have been demonstrated to improve the efficacy of conversion therapy by identifying individualtargeted effective drugs,but their clinical effects in liver cancer remain unknown.CASE SUMMARY We described a patient with hepatocellular carcinoma(HCC)who achieved pathologic complete response(pCR)to conversion therapy guided by the patientderived organoid(PDO)drug sensitivity testing.Despite insufficiency of the remaining liver volume after hepatectomy,the patient obtained tumor reduction after treatment with the PDO-sensitive drugs and successfully underwent radical surgical resection.Postoperatively,pCR was observed.CONCLUSION PDOs contributes to screening sensitive drugs for HCC patients to realize the personalized treatment and improve the conversion therapy efficacy.

Novel biomarkers GEP/ABCB5 regulate response to adjuvant transarterial chemoembolization after curative hepatectomy for hepatocellular carcinoma

Background: Transarterial chemoembolization(TACE) is the most commonly used adjuvant therapy for hepatocellular carcinoma(HCC) after curative resection. Responses to TACE are variable due to tumor and patient heterogeneity. We had previously demonstrated that expression of Granulin-epithelin precursor(GEP) and ATP-dependent binding cassette(ABC)B5 in liver cancer stem cells was associated with chemoresistance. The present study aimed to evaluate the association between GEP/ABCB5 expression and response to adjuvant TACE after curative resection for HCC. Methods: Patients received adjuvant TACE after curative resection for HCC and patients received curative resection alone were identified from a prospectively collected database. Clinical samples were retrieved for biomarker analysis. Patients were categorized into 3 risk groups according to their GEP/ABCB5 status for survival analysis: low(GEP-/ABCB5-), intermediate(either GEP +/ABCB5-or GEP-/ABCB5 +) and high(GEP +/ABCB5 +). Early recurrence(recurrence within 2 years after resection) and disease-free survival were analyzed. Results: Clinical samples from 44 patients who had followed-up for more than 2 years were retrieved for further biomarker analysis. Among them, 18 received adjuvant TACE and 26 received surgery alone. Patients with adjuvant TACE in the intermediate risk group was associated with significantly better overall survival and 2-year disease-free survival than those who had surgery alone( P = 0.036 and P = 0.011, respectively). Adjuvant TACE did not offer any significant differences in the early recurrence rate, 2-year disease-free survival and overall survival for patients in low and high risk groups. Conclusions: Adjuvant TACE can only provide survival benefits for patients in the intermediate risk group(either GEP +/ABCB5-or GEP-/ABCB5 +). A larger clinical study is warranted to confirm its role in patient selection for adjuvant TACE.

Analysis of serious complications of transcatheter arterial chemoembolization for the treatment of hepatocellular carcinoma

Objective: To analyze the inductive agents, post-surgical managements and precautions of the serious complications caused by transcatheter arterial chemoembolization (TACE) for the treatment of hepatocellular carcinoma. Methods: Clinical data of 2 375 cases of TACE for 832 patients with middle-stage or advanced hepatocellular carcinoma from January 1994 to December 2002 were analyzed. Results: There were 7 cases of serious complications, one of which was liver carcinoma rupture and another was acute renal failure. Totally there were 4 cases of paraplegia and one case of conduit knotted. Conclusion: Deadly complications may happen after TACE and it needs close surveillance and management in time.

Interferon plus ribavirin and interferon alone in preventing hepatocellular carcinoma: A prospective study on patients with HCV related cirrhosis

AIM:To determine the role of interferon(IFN)with or withoutribavirin in preventing or delaying hepatocellular carcinoma(HCC)development in patients with hepatitis C virus(HCV)related cirrhosis.Data on the preventive effect of IFN plusribavirin treatment are lacking.METHODS:A total of 101 patients(62 males and 39 females,mean age 55.1±1.4 years)with histologically proven HCVrelated liver cirrhosis plus compatible biochemistry andultrasonography were enrolled in the study.Biochemistryand ultrasonography were performed every 6 mo.Ultrasoundguided liver biopsy was performed on all detected focallesions.Follow-up lasted for 5 years.Cellular proliferation,evaluated by measuring Ag-NOR proteins in hepatocytesnuclei,was expressed as AgNOR-Proliferative index(AgNOR-PI)(cut-off=2.5).Forty-one patients(27 males,14 females)were only followed up after the end of anyearly treatment with IFN-alpha2b(old treatment controlgroup=OTCG).Sixty naive patients were stratified accordingto sex and AgNOR-PI and then randomized in two groups:30 were treated with IFN-alpha2b+ribavirin(treatmentgroup=TG),the remaining were not treated(control group=CG).Nonresponders(NR)or relapsers in the TG receivedfurther IFN/ribavirin treatments after a 6 mo of withdrawal.RESULTS:AgNOR-PI was significantly lowered by IFN(P<0.001).HCC incidence was higher in patients withAgNOR-PI>2.5(26% vs3%,P<0.01).Two NR in the OTCG,none in the TG and 9 patients in the CG developed HCCduring follow-up.The Kaplan-Mayer survival curves showedstatistically significant differences both between OTCG andCG(P<0.004)and between TG and CG(P<0.003).CONCLUSION:IFN/ribavirin treatment associated with re-treatment courses of NR seems to produce the best resultsin terms of HCC prevention.AgNOR-PI is a useful markerof possible HCC development.

Uterine papillary serous carcinoma: Its clinical and fundamental studyUterine papillary serous carcinoma: Its clinical and fundamental study

Uterine papillary serous carcinoma(UPSC) was established as a distinct type of endometrial carcinoma by Lauchlan in 1981 and Hendrickson et al in 1982, and ac- counted for 1 % - 10% of endometrial cancers. The occurrencer of papillary patterns of en- dometrial adenocarcinoma had been reportedly recognized since 1900, while until the late 1970s several authors have had described a variant of papillary endometrial cancer. UPSC is a morphologically unique variant of endometrial carcinoma that is pathologically defined by the presence of high nuclear grade, distinct papillary architechtural changes, psammoma bodies, and extensive lymph - vascular space invasion. CA125 is often mentioned a useful tumor marker either for diagnosis before starting treatment or in monitoring recurrence. The optimal treatment of UPSC is controversial and appears to be dependent upon the stage of the disease. Primary surgery comprised of TAH/BSO and complete staging is the mainstay of treatment. The patients with recurrent UPSC in many studies were treated with various combinations of surgery , radiation therapy, and chemotherapy. The molecular basis for the gneeral poor response of UPSC to adjuvant chemotherapy and radiotherapy is not well under- stood. UPSC tumors are more often aneuploid and contain overexpressed mutant p53 protein as compared to endometrioid adenocarcinoma. Unlike patients with adenocarcinoma of the endometrium, women with UPSC were less likely to be obese, hypertensive, or diabetic.

Hepatocellular carcinoma immunotherapy:The impact of epigenetic drugs and the gut microbiome

The incidence of hepatocellular carcinoma(HCC)has been increasing for decades.This disease has now risen to become the sixth most common malignancy overall,while ranking as the third most frequent cause of cancer mortality.While several surgical interventions and loco-regional treatment options are available,up to 80%of patients present with advanced disease not amenable to standard therapies.Indeed,traditional cytotoxic chemotherapeutic agents are notoriously ineffective and essentially play no role in the management of affected patients.This has led to an enormous need for more effective sys-temic therapeutic options.In recent years,immunotherapy has emerged as a potentially viable and exciting new alternative for the treatment of HCC.Although the current immunotherapeutic options remain imperfect,various strategies can be employed to further improve their efficacy.New findings have revealed epigenetic modulation can be effective as a new approach for improving HCC immuno-therapy.Studying the gut microbiome(gut-liver axis)can also be an interesting subject in this regard.Here,we explore the latest insights into the role of immunotherapy treating HCC,both mono and in combination with other agents.We also focus on the impact of epigenetic drugs and the microbiome in the overall effectiveness of HCC immunotherapy.