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Background: The effect of age, sex, and eastern cooperative oncology group performance status (ECOG PS) on the efficacy and safety of immune checkpoint inhibitor (ICI) therapy among hepatocellular carcinoma (HCC) patients remains elusive. Thus, a meta-analysis was conducted to evaluate whether such effects exist., Research Design and Methods: Eligible studies in PubMed, Embase, and Cochrane Library databases were retrieved., Results: One-hundred-and-eleven studies involving 14,768 HCC patients were included. The findings indicated that the ECOG PS didn't have a significant effect on the ORR and PFS in ICI-treated HCC patients (higher ECOG PS vs. lower ECOG PS: ORR: OR  = 0.78, 95%CI = 0.55-1.10; PFS: HR  = 1.15, 95%CI = 0.97-1.35), while those patients with a higher ECOG PS may have a worse OS ( HR  = 1.52, 95% CI = 1.26-1.84). There is no significant evidence of the effect of age (older vs. younger) or sex (males vs. females) on the efficacy of ICI therapy in HCC., Conclusion: ICI therapy in HCC should not be restricted strictly to certain patients in age or sex categories, while HCC patients with higher ECOG PS may require closer medication or follow-up strategy during ICI therapy., Prospero Registration: CRD42024518407.

Background: The prognostic value of alpha-fetoprotein (AFP) response for efficacy of targeted therapy or immune checkpoint inhibitors (ICIs) has not been established. The purpose of this meta-analysis is to elucidate the relationship between AFP response and survival outcomes in hepatocellular carcinoma (HCC) patients who received targeted therapy or ICIs., Methods: The hazard ratio (HR) with 95% confidence interval (CI) was used to evaluate the relationship between AFP response and overall survival (OS)/progression-free survival (PFS)., Results: Twenty-six articles containing 3056 HCC patients were finally included in the study. The pooled results showed that after targeted therapy or ICIs, patients with decrease in AFP had better prognosis (OS:HR = 0.48, 95%CI:0.40-0.56; PFS:HR = 0.39, 95%CI:0.33-0.46), while patients with increase in AFP had worse prognosis (OS:HR = 2.30, 95%CI:1.82-2.89; PFS:HR = 2.34, 95%CI = 1.69-3.24). Subgroup analysis revealed that compared to AFP decrease >50%, AFP decrease >20% can better predict the prognosis of patients who received targeted therapy (OS:HR = 0.51, 95%CI:0.41-0.62; PFS:HR = 0.39, 95%CI:0.30-0.51) or ICIs treatment (OS:HR = 0.34, 95%CI:0.16-0.71; PFS:HR = 0.22, 95%CI:0.10-0.47), and 8 weeks after targeted therapy may be the appropriate time point for AFP assessment., Conclusion: AFP decrease >20% within 8 weeks may be the appropriate definition for early AFP response which probably works best in predicting the efficacy of therapy., Registration: The review was not registered.

Objective: This meta-analysis was designed to explore the association between the systemic immune-inflammation index (SII) and the therapeutic effect of immune checkpoint inhibitors. Materials & methods: The authors retrieved relevant studies published before May 25, 2022. Hazard ratio (HR) with 95% CI was used to evaluate the relationship between SII and overall survival (OS) and progression-free survival (PFS). Results: 14 articles comprising 2721 patients were included in this study. The pooled results proved that high SII levels were closely related to poor prognosis in cancer patients receiving immune checkpoint inhibitors (OS HR = 2.40; 95% CI: 2.04-2.82; PFS HR = 1.57; 95% CI: 1.33-1.86) and that an SII value of 750 was appropriate as a cut-off value (OS HR = 2.20; 95% CI: 1.83-2.63; PFS HR = 1.54; 95% CI: 1.33-1.80). Conclusion: High SII levels (>750) may be an indicator of worse OS and PFS in cancer patients treated with immune checkpoint inhibitors.

Background and aims: The impacts of macrovascular invasion (MVI) or extrahepatic spread (EHS) on the efficacy and safety of immune checkpoint inhibitors (ICIs) among hepatocellular carcinoma (HCC) patients remain unclear. Thus, we conducted a systematic review and meta-analysis to clarify whether ICI therapy is a feasible treatment option for HCC with MVI or EHS. Methods: Eligible studies published before September 14, 2022, were retrieved. In this meta-analysis, the objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and occurrence of adverse events (AEs) were outcomes of interest. Results: Fifty-four studies involving 6187 individuals were included. The findings indicated that the presence of EHS in ICI-treated HCC patients may indicate an inferior ORR (OR 0.77, 95% CI 0.63–0.96), but may not significantly affect the PFS (multivariate analyses: HR 1.27, 95% CI 0.70–2.31) and OS (multivariate analyses: HR 1.23, 95% CI 0.70–2.16). Additionally, the presence of MVI in ICI-treated HCC patients may not have significant prognostic impact on ORR (OR 0.84, 95% CI 0.64–1.10), but may indicate inferior PFS (multivariate analyses: HR 1.75, 95% CI 1.07–2.84) and OS (multivariate analyses: HR 2.03, 95% CI 1.31–3.14). The presence of EHS or MVI in ICI-treated HCC patients may not significantly impact the occurrence of any serious immune-related adverse events (irAEs) (grades ≥ 3) (EHS: OR 0.44, 95% CI 0.12–1.56; MVI: OR 0.68, 95% CI 0.24–1.88). Conclusion: The presence of MVI or EHS in ICI-treated HCC patients may not significantly impact the occurrence of serious irAEs. However, the presence of MVI (but not EHS) in ICI-treated HCC patients may be a significant negative prognostic factor. Therefore, ICI-treated HCC patients with MVI warrant more attention. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma is one of the most lethal malignancies, having a significantly poor prognosis. Immunotherapy, as an emerging tumor treatment option, provides new hope for many cancer patients. However, a large proportion of patients do not benefit from immunotherapy. As a critical cell-to-cell communication mediator in the tumor immune microenvironment, exosomes may play a unique role in hepatocellular carcinoma immune response and thus affect the efficiency of immunotherapy. In this review, we discuss related research on the roles of exosomes in the current immunotherapy resistance mechanism of hepatocellular carcinoma. Furthermore, we also clarify the excellent predictive value of exosomes and the roles they play in improving immunotherapy efficacy for hepatocellular carcinoma patients. We hope that our review can help readers to gain a more comprehensive understanding of exosomes' roles in hepatocellular carcinoma immunotherapy. Hepatocellular carcinoma (HCC) is one of the most lethal malignancies, having a significantly poor prognosis and no sufficiently efficient treatments. Immunotherapy, especially immune checkpoint inhibitors (ICIs), has provided new therapeutic approaches for HCC patients. Nevertheless, most patients with HCC do not benefit from immunotherapy. Exosomes are biologically active lipid bilayer nano-sized vesicles ranging in size from 30 to 150 nm and can be secreted by almost any cell. In the HCC tumor microenvironment (TME), numerous cells are involved in tumor progression, and exosomes—derived from tumor cells and immune cells—exhibit unique composition profiles and act as intercellular communicators by transporting various substances. Showing the dual characteristics of tumor promotion and suppression, exosomes exert multiple functions in shaping tumor immune responses in the crosstalk between tumor cells and surrounding immune cells, mediating immunotherapy resistance by affecting the PD-1/PD-L1 axis or the anti-tumor function of immune cells in the TME. Targeting exosomes or the application of exosomes as therapies is involved in many aspects of HCC immunotherapies (e.g., ICIs, tumor vaccines, and adoptive cell therapy) and may substantially enhance their efficacy. In this review, we discuss the impact of exosomes on the HCC TME and comprehensively summarize the role of exosomes in immunotherapy resistance and therapeutic application. We also discuss the potential of exosomes as biomarkers for predicting the efficacy of immunotherapy to help clinicians in identifying HCC patients who are amenable to immunotherapies. [ABSTRACT FROM AUTHOR]

• The RET gene, which is frequently mutated across many cancer types, has been proven to be involved in tumorigenesis. • However, its prediction of the therapeutic efficacy of immune checkpoint inhibitor (ICIs) therapy remains to be elucidated. • The present research aims to investigate the association between RET mutations and the efficiency of ICIs therapy. The RET gene, which is frequently mutated across many types of cancer, has been proven to be critically involved in tumorigenesis and tumour development; however, its prediction of the therapeutic efficacy of immune checkpoint inhibitor (ICI) therapy remains to be elucidated. The present research aims to investigate the association between RET mutations and the efficiency of ICI therapy. We analysed the role of RET mutations in predicting the prognosis of patients receiving ICIs therapy in the discovery cohort and validated it in the validation cohort. Then, multi-omics data from TCGA pan-cancer cohort was employed to propose the association between RET mutations and tumour inflamed anti-tumour immune response and tumour antigenicity. Our study revealed that among 606 cases and across five types of cancer, RET mutation was associated with better clinical outcomes for ICIs therapy, including elevated response rate, longer progression-free survival PFS, and longer overall survival OS. Multivariate analysis showed that RET mutation could independently predict the prognosis of patients treated with ICIs, after adjusting cancer types. The predictive value of RET status for the OS of patients treated with ICIs immunotherapy was further validated in the validation cohort (n = 1,409). Subgroup analysis suggested that only the monotherapy group showed significant differences in OS(P < 0.05) and PFS(P < 0.05) between RET -wildtype tumours and RET -mutant tumours. Multi-omics data analysis revealed potential anti-tumour immunity mechanisms of RET mutations, suggesting that RET -mutant tumours have enhanced immunogenicity, higher expression of immune checkpoints and chemokines, and higher immune cell infiltration than those observed in RET -wildtype tumours; thus, potentially indicating a more favourable response to immunotherapy. RET mutation may be a predictive biomarker of enhanced response to ICIs therapy. Extensive investigation of the underlying molecular mechanisms and prospective studies are needed in the future. [ABSTRACT FROM AUTHOR]

• Hepatocellular carcinoma patients with impaired liver function have poor prognosis after receiving ICIs. • Both ALBI score and Child-Pugh score can stratify HCC patients. • ALBI score is simpler and more reliable for patient stratification than Child-Pugh score. • The incidence of adverse events is not significantly increased in impaired liver function patients. Most patients with hepatocellular carcinoma (HCC) have underlying cirrhosis and a compromised liver function. Immune checkpoint inhibitors (ICIs) have emerged as an important approach for HCC treatment. The purpose of our study was to explore the prognostic significance of liver function in HCC patients receiving ICIs. Hazard ratios (HR) with 95% confidence intervals (CI) were used to evaluate the relationship between liver function and overall survival (OS)/progression-free survival (PFS). 41 articles with 4483 patients with HCC were included. The pooled results revealed that either Child-Pugh score (OS:HR = 2.01,95 %CI:1.69–2.38; PFS:HR = 1.39,95 %CI:1.15–1.68) or albumin-bilirubin (ALBI) score (OS:HR = 2.04,95 %CI:1.55–2.69; PFS:HR = 1.42,95 %CI:1.21–1.67) can predict the patient prognosis. The Child-Pugh score has some degree of subjectivity, and the ALBI score can better stratify patients. Therefore, the ALBI score was used to evaluate patients' liver function and determine treatment options. Further subgroup analysis found that the results of prospective studies were statistically significant only for the ALBI score with regards to OS (HR = 1.69,95 %CI:1.26–2.26). Meanwhile, the effect of liver function on the efficacy of ICIs in the large-sample studies was not as obvious as that in small-sample studies. Moreover, the incidence of adverse events did not significantly increase in patients with impaired liver function. Poor liver function is associated with a poor prognosis in patients with HCC receiving ICIs. The ALBI score is simpler and reliable for patient stratification than the Child-Pugh score. Although the survival time of patients with impaired liver function may be relatively short, ICIs still have great potential for therapeutic applications. [ABSTRACT FROM AUTHOR]